Tricyclic inhibitors of hydroxysteroid dehydrogenases

ABSTRACT

The present invention provides tricyclic compounds according to formula (I): (I) where R 1 , R 2 , R 3 , W, X, Y, Z, m, n, and p are as defined in the description; as well as pharmaceutical compositions comprising the same, methods of use of the compounds and compositions of the invention for the treatment of conditions associated with hydroxysteroid dehydrogenases (e.g., 11-HSD1), and the use of the compounds of the invention in the preparation of medicaments for the treatment of hydroxysteroid dehydrogenase-associated conditions.

BACKGROUND OF THE INVENTION

The present invention is generally directed to novel compounds,compositions, and the use of either in methods for modulatinghydroxysteroid dehydrogenases, such as 11β-HSD1, and for treating orpreventing diseases associated with the modulation of hydroxysteroiddehydrogenases, such as diabetes and obesity. The methods comprise theadministration, to a patient in need thereof, of a therapeuticallyeffective amount of a tricyclic compound. Novel tricyclic compounds orpharmaceutically acceptable salts, solvates, stereoisomers, or prodrugsthereof are presented herein.

Hydroxysteroid dehydrogenases (HSDs) regulate the occupancy andactivation of steroid hormone receptors by converting steroid hormonesinto their inactive metabolites. For a recent review, see Nobel et al.,Eur. J. Biochem. 2001, 268:4113-4125.

There exist numerous classes of HSDs. The 11-beta-hydroxysteroiddehydrogenases (11β-HSDs) catalyze the interconversion of activeglucocorticoids (such as cortisol and corticosterone), and their inertforms (such as cortisone and 11-dehydrocorticosterone). The isoform11-beta-hydroxysteroid dehydrogenase type 1 (11β-HSD1) is expressed inliver, adipose tissue, skeletal muscle, bone, brain, lung, and otherglucocorticoid tissues and is a potential target for therapy directed atnumerous disorders that may be ameliorated by reduction ofglucocorticoid action, such as diabetes, obesity, and age-relatedcognitive dysfunction. Seckl et al., Endocrinology 2001, 142:1371-1376.

It is well known that glucocorticoids play a central role in thedevelopment of diabetes and that glucocorticoids enable the effect ofglucagon on the liver. Long et al., J. Exp. Med. 1936, 63:465-490; andHoussay, Endocrinology 1942, 30:884-892. In addition, it has been wellsubstantiated that 11β-HSD1 plays an important role in the regulation oflocal glucocorticoid effect and of glucose production in the liver.Jamieson et al., J. Endocrinol. 2000, 165:685-692.

Furthermore, the hypothesized mechanism of action of HSDs in thetreatment of diabetes has been supported by various experimentsconducted in mice and rats. These studies showed that the mRNA levelsand activities of two key enzymes in hepatic glucose production,phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase(G6Pase), were reduced upon administration of HSD inhibitors. Inaddition, blood glucose levels and hepatic glucose production were shownto be reduced in 11β-HSD1 knockout mice. Additional data gathered usingthis murine knockout model also confirm that inhibition of 11β-HSD1 willnot cause hypoglycemia, since the basal levels of PEPCK and G6 Pase areregulated independently of glucocorticoids. Kotelevtsev et al., Proc.Natl. Acad. Sci. USA 1997, 94:14924-14929.

HSDs also play a role in obesity. Obesity is an important factor inSyndrome X as well as type II (non-insulin-dependent) diabetes, andomental fat appears to be of central importance in the development ofboth of these diseases, as abdominal obesity has been linked withglucose intolerance, hyperinsulinemia, hypertriglyceridemia, and otherfactors of Syndrome X (e.g., raised blood pressure, decreased levels ofHDL, and increased levels of VLDL). Montague et al., Diabetes 2000,49:883-888. It has also been reported that inhibition of the 11β-HSDs inpre-adipocytes (stromal cells) resulted in a decreased rate ofdifferentiation into adipocytes. This is predicted to result indiminished expansion (possibly reduction) of the omental fat depot,which may lead to reduced central obesity. Bujalska et al., Lancet 1997,349:1210-1213.

Inhibition of 11β-HSD1 in mature adipocytes is expected to attenuatesecretion of the plasminogen activator inhibitor 1 (PAI-1), which is anindependent cardiovascular risk factor, as reported in Halleux et al.,J. Clin. Endocrinol. Metab. 1999, 84:4097-4105. In addition, acorrelation has been shown to exist between glucocorticoid activity andcertain cardiovascular risk factors. This suggests that a reduction ofthe glucocorticoid effects would be beneficial in the treatment orprevention of certain cardiovascular diseases. Walker et al.,Hypertension 1998, 31:891-895; and Fraser et al., Hypertension 1999,33:1364-1368.

HSDs have also been implicated in the process of appetite control andtherefore are believed to play an additional role in weight-relateddisorders. It is known that adrenalectomy attenuates the effect offasting to increase both food intake and hypothalamic neuropeptide Yexpression. This suggests that glucocorticoids play a role in promotingfood intake and that inhibition of 11β-HSD1 in the brain may increasesatiety, thus resulting in decreased food intake. Woods et al., Science1998, 280:1378-1383.

Another possible therapeutic effect associated with modulation of HSDsis that which is related to various pancreatic aliments. It is reportedthat inhibition of 11β-HSD1 in murine pancreatic β-cells results inincreased insulin secretion. Davani et al., J. Biol. Chem. 2000,275:34841-34844. This follows from the discovery that glucocorticoidswere previously found to be responsible for reduced pancreatic insulinrelease in vivo. Billaudel et al., Horm. Metab. Res. 1979, 11:555-560.Thus, it is suggested that inhibition of 11β-HSD1 would yield otherbeneficial effects in the treatment of diabetes other than the predictedeffects on the liver and fat reduction.

11β-HSD1 also regulates glucocorticoid activity in the brain and thuscontributes to neurotoxicity. Rajan et al., Neuroscience 1996, 16:65-70;and Seckl et al., Neuroendocrinol. 2000, 18:49-99. Stress and/orglucocorticoids are known to influence cognitive function (de Quervainet al., Nature 1998, 394:787-790), and unpublished results indicatesignificant memory improvement in rats treated with a non-specific11β-HSD inhibitor. These reports, in addition to the known effects ofglucocorticoids in the brain, suggest that inhibiting HSDs in the brainmay have a positive therapeutic effect against anxiety and relatedconditions. Tronche et al., Nature Genetics 1999, 23:99-103. 11β-HSD1reactivates 11-DHC to corticosterone in hippocampal cells and canpotentiate kinase neurotoxicity, resulting in age-related learningimpairments. Therefore, selective inhibitors of 11β-HSD1 are believed toprotect against decline of hippocampal function with age. Yau et al.,Proc Natl. Acad. Sci. USA 2001, 98:4716-4721. Thus, it has beenhypothesized that inhibition of 11β-HSD1 in the human brain wouldprotect against deleterious glucocorticoid-mediated effects on neuronalfunction, such as cognitive impairment, depression, and increasedappetite.

HSDs are believed to play a role in immunomodulation based on thegeneral perception that glucocorticoids suppress the immune system.There is known to be a dynamic interaction between the immune system andthe HPA (hypothalamopituitary-adrenal) axis (Rook, Baillier's Clin.Endocrinol. Metab. 2000, 13:576-581), and glucocorticoids help balancecell-mediated responses and humoral responses. Increased glucocorticoidactivity, which may be induced by stress, is associated with a humoralresponse and as such, inhibition of 11β-HSD1 may result in shifting theresponse towards a cell-based reaction. In certain disease states, suchas tuberculosis, leprosy, and psoriasis, the immune reaction istypically biased toward a humoral response when a cell-based responsemight be more appropriate. Inhibition of 11β-HSD1 is being studied foruse to direct a cell-based response in these instances. Mason,Immunology Today 1991, 12:57-60. It follows then that an alternativeutility of 11β-HSD1 inhibition would be to bolster a temporal immuneresponse in association with immunization to ensure that a cell-basedresponse would be obtained.

Recent reports suggest that the levels of glucocorticoid targetreceptors and HSDs are connected with the risks of developing glaucoma.Stokes et al., Invest. Opthalmol. 2000, 41:1629-1638. Further, aconnection between inhibition of 11β-HSD1 and lowering of intraocularpressure was reported. Walker et al., poster P3-698 at the EndocrineSociety meeting Jun. 12-15, 1999, San Diego. It was shown thatadministration of the nonspecific 11β-HSD1 inhibitor, carbenoxolone,resulted in reduction of intraocular pressure by 20% in normal patients.In the eye, 11β-HSD1 is expressed exclusively in the basal cells of thecorneal epithelium, the non-pigmented epithelialium of the cornea (thesite of aqueous production), ciliary muscle, and the sphincter anddilator muscles of the iris. In contrast, the distant isoenzyme11β-hydroxysteroid dehydrogenase type 2 (“11β-HSD2”) is highly expressedin the non-pigmented ciliary epithelium and corneal endothelium. No HSDshave been found at the trabecular meshwork, which is the site ofdrainage. Therefore, 11β-HSD1 is suggested to have a role in aqueousproduction.

Glucocorticoids also play an essential role in skeletal development andfunction, but are detrimental to such development and function whenpresent in excess. Glucocorticoid-induced bone loss is partially derivedfrom suppression of osteoblast proliferation and collagen synthesis. Kimet al., J. Endocrinol. 1999, 162:371-379. It has been reported that thedetrimental effects of glucocorticoids on bone nodule formation can belessened by administration of carbenoxolone, which is a non-specific11β-HSD1 inhibitor. Bellows et al., Bone 1998, 23:119-125. Additionalreports suggest that 11β-HSD1 may be responsible for providing increasedlevels of active glucocorticoid in osteoclasts, and thus in augmentingbone resorption. Cooper et al., Bone 2000, 27:375-381. This datasuggests that inhibition of 11β-HSD1 may have beneficial effects againstosteoporosis via one or more mechanisms which may act in parallel.

It is known that bile acids inhibit 11β-HSD2 and that such inhibitionresults in a shift in the cortisol/cortisone equilibrium in the favor ofcortisol. Quattropani et al., J. Clin. Invest. November 2001,108:1299-305. A reduction in the hepatic activity of 11β-HSD2 istherefore predicted to reverse the cortisol/cortisone equilibrium tofavor cortisone, which could provide therapeutic benefit in diseasessuch as hypertension.

The various isozymes of the 17-beta-hydroxysteroid dehydrogenases(17β-HSDs) bind to androgen receptors or estrogen receptors and catalyzethe interconversion of various sex hormones, including estradiol/estroneand testosterone/androstenedione. To date, six isozymes have beenidentified in humans and are expressed in various human tissues,including endometrial tissue, breast tissue, colon tissue, and thetestes. 17-beta-Hydroxysteroid dehydrogenase type 2 (17β-HSD2) isexpressed in human endometrium and its activity has been reported to belinked to cervical cancer. Kitawaki et al., J. Clin. Endocrin. Metab.2000, 85:3292-3296. 17-beta-Hydroxysteroid dehydrogenase type 3(17β-HSD3) is expressed in the testes and its modulation may be usefulfor the treatment of androgen-related disorders.

Androgens and estrogens are active in their 17β-hydroxy configurations,whereas their 17-keto derivatives do not bind to androgen and estrogenreceptors and are thus inactive. The conversion between the active andinactive forms (estradiol/estrone and testosterone/androstenedione) ofsex hormones is catalyzed by members of the 17β-HSD family. 17β-HSD1catalyzes the formation of estradiol in breast tissue, which isimportant for the growth of malignant breast tumors. Labrie et al., Mol.Cell. Endocrinol. 1991, 78:C113-C118. A similar role has been suggestedfor 17β-HSD4 in colon cancer. English et al., J. Clin. Endocrinol.Metab. 1999, 84:2080-2085. 17β-HSD3 is almost exclusively expressed inthe testes and converts androstenedione into testosterone. Deficiency ofthis enzyme during fetal development leads to malepseudohermaphroditism. Geissler et al., Nat. Genet. 1994, 7:34-39.17β-HSD3 and various 3α-HSD isozymes are involved in complex metabolicpathways which lead to shuffles between inactive and active forms ofandrogen. Penning et al., Biochem. J. 2000, 351:67-77. Thus, modulationof certain HSDs can have potentially beneficial effects in the treatmentof androgen- and estrogen-related disorders.

The 20-alpha-hydroxysteroid dehydrogenases (20α-HSDs) catalyze theinterconversion of progestins (such as between progesterone and20α-hydroxy progesterone). Other substrates for 20α-HSDs include17α-hydroxypregnenolone and 17α-hydroxyprogesterone, leading to 20α-OHsteroids. Several 20α-HSD isoforms have been identified and 20α-HSDs areexpressed in various tissues, including the placenta, ovaries, testes,and adrenals. Peltoketo et al., J. Mol. Endocrinol. 1999, 23:1-11.

The 3-alpha-hydroxysteroid dehydrogenases (3α-HSDs) catalyze theinterconversion of the androgens dihydrotestosterone (DHT) and5α-androstane-3α,17β-diol and the interconversion of the androgens DHEAand androstenedione. Consequently, 3α-HSDs play an important role inandrogen metabolism. Ge et al., Biology of Reproduction 1999,60:855-860.

Despite the previous research done in the field of HSD inhibition, thereremains a need for novel compounds that are potent inhibitors of thevarious families of HSDs and efficacious for the treatment ofHSD-mediated conditions such as diabetes, obesity, glaucoma,osteoporosis, cognitive disorders, immune disorders, depression,hypertension, and others.

SUMMARY OF THE INVENTION

In brief, the present invention relates to novel compounds, compositionsthereof and methods for modulating the activity of hydroxysteroiddehydrogenases (HSDs), such as 11β-hydroxysteroid dehydrogenases,17β-hydroxysteroid dehydrogenases, 20α-hydroxysteroid dehydrogenases,and 3α-hydroxysteroid dehydrogenases, including all isoforms thereof,including but not limited to 11β-hydroxysteroid dehydrogenase type 1(hereinafter “11β-HSD1”), 11β-hydroxysteroid dehydrogenase type 2(hereinafter “11β-HSD2”), and 17β-hydroxysteroid dehydrogenase type 3(hereinafter “17β-HSD3”). In one embodiment, the compounds of theinvention inhibit HSD activity.

The present invention also relates to methods for treating or preventingdiseases or disorders associated with the action of hydroxysteroiddehydrogenases, comprising administering to a patient in need thereof atherapeutically effective amount of a tricyclic compound or apharmaceutically acceptable salt, solvate, stereoisomer, or prodrugthereof, or a mixture thereof. The invention encompasses both selectiveand non-selective inhibitors of hydroxysteroid dehydrogenases.

It should be understood that selective and non-selective inhibitors ofhydroxysteroid dehydrogenases each have benefits in the treatment orprevention of diseases associated with, for example, abnormal glucoselevels or hypothalmic function. The invention also encompasses selectiveinhibitors of HSDs. Two types of selectivity are contemplated, that withrespect to selectivity for HSDs as a class over other types of receptorsor gene targets related to glucose metabolism, or that with respect toselectivity for various HSDs or specific isoforms thereof compared toother HSDs or specific isoforms thereof.

In one embodiment, the tricyclic compounds can act as selective ornon-selective 11β-HSD inhibitors. The compounds may inhibit theinterconversion of inactive 11-keto steroids with their active hydroxyequivalents. The present invention provides methods by which theconversion of the inactive to the active form may be controlled, and isdirected to useful therapeutic effects which may be obtained as a resultof such control. More specifically, but not exclusively, the inventionis concerned with interconversion between cortisone and cortisol inhumans.

In another embodiment, the tricyclic compounds of the present inventionare orally active.

The tricyclic compounds are also useful for modulation of numerousmetabolic functions including, but not limited to, one or more of: (i)regulation of carbohydrate metabolism, (ii) regulation of proteinmetabolism, (iii) regulation of lipid metabolism, (iv) regulation ofnormal growth and/or development, (v) influence on cognitive function,and (vi) resistance to stress and mineralocorticoid activity.

The tricyclic compounds may also be useful for inhibiting hepaticgluconeogenesis, and may also be effective to relieve the effects ofendogenous glucocorticoids in diabetes mellitus, obesity (includingentripetal obesity), neuronal loss and/or the cognitive impairment ofold age. Thus, in a further embodiment, the invention provides the useof an inhibitor of HSDs in methods directed to producing one or moretherapeutic effects in a patient to whom the tricyclic compound isadministered, said therapeutic effects selected from the groupconsisting of inhibition of hepatic gluconeogenesis, an increase ininsulin sensitivity in adipose tissue and muscle, and prevention of orreduction in neuronal loss/cognitive impairment due toglucocorticoid-potentiated neurotoxicity or neural dysfunction ordamage.

The invention further provides methods for treating a condition selectedfrom the group consisting of hepatic insulin resistance, adipose tissueinsulin resistance, muscle insulin resistance, neuronal loss ordysfunction due to glucocorticoid potentiated neurotoxicity, and anycombination of the aforementioned conditions, the methods comprisingadministering to a patient in need thereof a therapeutically effectiveamount of a tricyclic compound.

The tricyclic compounds of the invention are compounds having formula(I)

or pharmaceutically acceptable salts, solvates, stereoisomers, orprodrugs thereof.

In one embodiment, each occurrence of R¹ and R² is independentlyhydrogen, halogen, nitro, cyano, (C₁-C₈)alkyl, (C₂-C₈)alkenyl,(C₂-C₈)alkynyl, (C₁-C₈)haloalkyl, (C₁-C₈)hydroxyhaloalkyl,(C₁-C₈)alkyl(C₃-C₇)cycloalkyl, (C₁-C₈)alkyl(C₃-C₇)heterocycloalkyl,(C₁-C₈)alkylaryl, (C₁-C₈)alkylheteroaryl, (C₃-C₇)cycloalkyl,(C₃-C₇)heterocycloalkyl, aryl, heteroaryl, —OR″, —C(O)R′, —C(O)OR′,—OC(O)R′, —OC(O)OR′, —C(O)N(R′)₂, —OC(O)N(R′)₂, —N(R′)₂, —NR′C(O)R′,—NR′C(O)OR″, —NR′C(O)N(R′)₂, —NR′SO₂R″, —SR″, —S(O)R″, —SO₂R″,—S(O)₂OR″, —SO₂N(R′)₂, -L-OR″, -L-C(O)R′, -L-C(O)OR′, -L-OC(O)R′,-L-OC(O)N(R′)₂, -L-N(R′)₂, -L-NR′C(O)OR″, -L-C(O)N(R′)₂, -L-NR′C(O)R″,-L-SR″, -L-S(O)R″, -L-SO₂R″, -L-SO₂N(R′)₂, or -L-NR′SO₂R″.

Each occurrence of R³ is independently null, hydrogen, halogen, nitro,cyano, (C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₁-C₈)haloalkyl,(C₁-C₈)alkyl(C₃-C₇)cycloalkyl, (C₁-C₈)alkyl(C₃-C₇)heterocycloalkyl,(C₁-C₈)alkylaryl, (C₁-C₈)alkylheteroaryl, (C₃-C₇)cycloalkyl,(C₃-C₇)heterocycloalkyl, —OR″, —C(O)R′, —C(O)OR′, —OC(O)R′, —OC(O)OR′,—C(O)N(R′)₂, —OC(O)N(R′)₂, —N(R′)₂, —NR′C(O)R′, —NR′C(O)OR″,—NR′C(O)N(R′)₂, —SR″, —S(O)R″, —SO₂R″, —S(O)₂OR″, —SO₂N(R′)₂, -L-OR″,-L-C(O)R′, -L-C(O)OR′, -L-OC(O)R′, -L-OC(O)N(R′)₂, -L-N(R′)₂,-L-C(O)N(R′)₂, -L-NR′C(O)R″, -L-SR″, -L-S(O)R″, -L-SO₂R″, -L-SO₂N(R′)₂,or -L-NR′SO₂R″.

W is C(R)₂, O, S, NR, NC(O)R′, NC(O)OR′, NC(O)N(R′)₂, or NS(O)₂R′.

X, Y, and Z are independently C, N, O, or S.

Each occurrence of R is independently hydrogen, halogen, cyano,(C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₁-C₈)haloalkyl,(C₁-C₈)hydroxyhaloalkyl, (C₁-C₈)alkyl(C₃-C₇)cycloalkyl,(C₁-C₈)alkyl(C₃-C₇)heterocycloalkyl, (C₁-C₈)alkylaryl,(C₁-C₈)alkylheteroaryl, (C₃-C₇)cycloalkyl, (C₃-C₇)heterocycloalkyl,aryl, heteroaryl, —OR″, —C(O)R′, —C(O)OR′, —OC(O)R′, —OC(O)OR′,—C(O)N(R′)₂, —OC(O)N(R′)₂, —N(R′)₂, —NR′C(O)R′, —NR′C(O)OR″,—NR′C(O)N(R′)₂, —NR′SO₂R″, —SR″, —S(O)R″, —SO₂R″, —S(O)₂OR″, —SO₂N(R′)₂,-L-OR″, -L-C(O)R′, -L-C(O)OR′, -L-OC(O)R′, -L-OC(O)N(R′)₂, -L-N(R′)₂,-L-NR′C(O)OR″, -L-C(O)N(R′)₂, -L-NR′C(O)R″, -L-SR″, -L-S(O)R″, -L-SO₂R″,-L-SO₂N(R′)₂, or -L-NR′SO₂R″.

Each occurrence of R′ is independently hydrogen, (C₁-C₈)alkyl,(C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₁-C₈)alkoxy(C₁-C₈)alkyl,(C₁-C₈)haloalkyl, (C₁-C₈)hydroxyalkyl, (C₁-C₈)hydroxyhaloalkyl,(C₁-C₈)alkyl(C₃-C₇)cycloalkyl, (C₁-C₈)alkyl(C₃-C₇)heterocycloalkyl,(C₁-C₈)alkylaryl, (C₁-C₈)alkylheteroaryl, (C₃-C₇)cycloalkyl,(C₃-C₇)heterocycloalkyl, aryl, or heteroaryl.

Alternatively, two R′ groups, when attached to the same nitrogen atom,can combine with the nitrogen atom to which they are attached to form aheterocyclic or heteroaryl group.

Each occurrence of R″ is independently hydrogen, (C₁-C₈)alkyl,(C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₁-C₈)alkoxy(C₁-C₈)alkyl,(C₁-C₈)haloalkyl, (C₁-C₈)hydroxyalkyl, (C₁-C₈)hydroxyhaloalkyl,(C₁-C₈)alkyl(C₃-C₇)cycloalkyl, (C₁-C₈)alkyl(C₃-C₇)heterocycloalkyl,(C₁-C₈)alkylaryl, (C₁-C₈)alkylheteroaryl, (C₃-C₇)cycloalkyl,(C₃-C₇)heterocycloalkyl, aryl, or heteroaryl.

Any cycloalkyl portion, heterocycloalkyl portion, aryl portion, orheteroaryl portion is optionally substituted with one to four membersselected from the group consisting of hydroxyl, halogen, cyano, nitro,(C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₁-C₈)alkoxy,(C₁-C₈)haloalkyl, (C₁-C₈)hydroxyalkyl, (C₁-C₈)hydroxyhaloalkyl, —OR″,—C(O)R′, —C(O)OR′, —OC(O)R′, —OC(O)OR′, —C(O)N(R′)₂, —OC(O)N(R′)₂,—N(R′)₂, —NR′C(O)R′, —NR′C(O)OR″, —NR′C(O)N(R″)₂, —NR′SO₂R″, —SR″,—S(O)R″, —SO₂R″, —S(O)₂OR″, —SO₂N(R′)₂, -L-OR″, -L-C(O)R′, -L-C(O)OR′,-L-OC(O)R′, -L-OC(O)N(R′)₂, -L-N(R′)₂, -L-NR′C(O)OR″, -L-C(O)N(R′)₂,-L-NR′C(O)R″, -L-SR″, -L-S(O)R″, -L-SO₂R″, -L-SO₂N(R′)₂, and-L-NR′SO₂R″.

L is (C₁-C₈)alkylene.

Variable m is an integer from 1 to 5.

Variable n is an integer from 0 to 2.

Variable p is an integer from 0 to 11.

In another embodiment of compounds of formula (I), at least oneoccurrence of R′ is other than hydrogen.

It should be understood that, notwithstanding the provisions of formula(I):

-   -   no occurrence of R′ is —SO₂NH₂, —SO₂NH-alkyl, or —SO₂-alkyl;    -   no occurrence of R² is —C(O)N(R′)₂, hydroxyalkyl, alkoxyalkyl,        or —CO₂H; and    -   no occurrence of R³ is hydroxyl, hydroxyalkyl, alkoxyalkyl,        —NH₂, —NH-alkyl, aminoalkyl, —C(O)O-alkyl, —C(O)-alkyl, or        -L—OC(O)-alkyl.

Furthermore, when X is S and Y is N, then no occurrence of R′ is:

-   -   cyano or nitro;    -   —OR″, —SR″, hydroxyalkyl, or —OC(O)-alkyl;    -   —NH₂, —NHR′, —N(alkyl)₂, —NR′C(O)R′, —NR′C(O)OR″, or        —NR′C(O)N(R′)₂; or    -   —C(O)-alkyl, —C(O)-aryl, —CO₂H, —C(O)O-alkyl, —C(O)N(R′)₂, or        -L-C(O)R′.

In addition, the following compounds are excluded from the scope of thepresent invention:

-   4-cyclohexyl-5-(3-fluorophenyl)-2-methyloxazole

-   4-cyclohexyl-2-ethyl-5-(3-fluorophenyl)oxazole

-   5-(4-chlorophenyl)-4-cyclopentyl-2-[(1S)-1-fluoroethyl]thiazole

-   5-(4-chlorophenyl)-4-cyclohexyl-2-ethylthiazole

-   4-cyclopentyl-2-ethyl-5-(4-ethylphenyl)thiazole

-   5-(3-chlorophenyl)-4-cyclopentyl-2-ethylthiazole

-   4-cyclopentyl-2-ethyl-5-(3-methylphenyl)thiazole

-   5-(2-chlorophenyl)-4-cyclopentyl-2-ethylthiazole

-   4-cyclopentyl-2-ethyl-5-(2-methylphenyl)thiazole

-   4-cyclohexyl-5-(3-fluorophenyl)-2-methyloxazole

-   3-[4-(4-fluorophenyl)-2-methyl-5-thiazolyl]-1-pyrrolidinecarboxylic    acid, ethyl ester

-   4-(4-fluorophenyl)-2-methyl-5-(3-pyrrolidinyl)thiazole

-   1-(4-fluorophenyl)-4-[3-[4-(4-fluorophenyl)-2-methyl-5-thiazolyl]-1-pyrrolidinyl]-1-butanone

-   4-(4-fluorophenyl)-5-[1-[3-[2-(4-fluorophenyl)-1,3-dioxolan-2-yl]propyl]-3-pyrrolidinyl]-2-methylthiazole

-   4-cyclohexyl-5-(3-fluorophenyl)-2-methyloxazole

-   4-[5-cyclohexyl-2-(methylthio)-4-thiazolyl]-2,6-bis(1,1-dimethylethyl)phenol

In one embodiment, the invention provides pharmaceutical compositionscomprising a tricyclic compound and a pharmaceutically acceptablevehicle, carrier, excipient, or diluent.

In another embodiment, the invention provides pharmaceuticalcompositions comprising a tricyclic compound and one or more additionaltherapeutic agents.

In a further embodiment, the invention provides a method for treating acondition or disorder selected from the group consisting of diabetes,syndrome X, obesity, polycystic ovarian disease, an eating disorder,craniopharyngioma, Prader-Willi syndrome, Frohlich's syndrome,hyperlipidemia, dyslipidemia, hypercholesterolemia,hypertriglyceridemia, low HDL levels, high HDL levels, hyperglycemia,insulin resistance, hyperinsulinemia, Cushing's syndrome, hypertension,atherosclerosis, vascular restenosis, retinopathy, nephropathy,neurodegenerative disease, neuropathy, muscle wasting, a cognitivedisorder, dementia, depression, psoriasis, glaucoma, osteoporosis, aviral infection, an inflammatory disorder, and an immune disorder,comprising administering to a patient in need thereof a therapeuticallyeffective amount of a tricyclic compound of formula (I).

In yet another embodiment, the invention provides a method for treatinga hydroxysteroid dehydrogenase-mediated condition or disorder,comprising administering to a patient in need thereof a therapeuticallyeffective amount of a compound of formula (I).

In a further embodiment, the invention provides a method for modulatinga hydroxysteroid dehydrogenase, comprising administering to a patient inneed thereof a therapeutically effective amount of a tricyclic compoundof formula (I).

In still another embodiment, the invention provides a method formodulating the function of a hydroxysteroid dehydrogenase in a cell,comprising contacting the cell with a tricyclic compound of formula (I).

In one embodiment, the invention provides a method for treating an11β-HSD1-mediated condition or disorder, comprising administering to apatient in need thereof a therapeutically effective amount of atricyclic compound of formula (I).

In another embodiment, the invention provides a method for modulatingthe function of 11β-HSD1 in a cell, comprising administering to apatient in need thereof a therapeutically effective amount of atricyclic compound of formula (I).

In a further embodiment, the invention provides a method for modulating11β-HSD1, comprising administering to a patient in need thereof atherapeutically effective amount of a tricyclic compound of formula (I).

These and other embodiments of the present invention will be evidentupon reference to the following detailed description. To that end,certain patent and other documents are cited herein to more specificallyset forth various embodiments of the present invention. Each of thesedocuments is hereby incorporated by reference in its entirety.

DETAILED DESCRIPTION

As used herein, the terms have the following meanings:

The term “alkyl” as used herein refers to a straight or branched chainsaturated hydrocarbon having the indicated number of carbon atoms. Forexample, (C₁-C₆)alkyl is meant to include, but is not limited to,methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl,isopentyl, neopentyl, hexyl, isohexyl, and neohexyl. An alkyl group canbe unsubstituted or optionally substituted with one or more substituentsas described herein below.

The term “alkenyl” as used herein refers to a straight or branched chainunsaturated hydrocarbon having the indicated number of carbon atoms andat least one double bond. Examples of a (C₂-C_(s))alkenyl group include,but are not limited to, ethylene, propylene, 1-butylene, 2-butylene,isobutylene, sec-butylene, 1-pentene, 2-pentene, isopentene, 1-hexene,2-hexene, 3-hexene, isohexene, 1-heptene, 2-heptene, 3-heptene,isoheptene, 1-octene, 2-octene, 3-octene, 4-octene, and isooctene. Analkenyl group can be unsubstituted or optionally substituted with one ormore substituents as described herein below.

The term “alkynyl” as used herein refers to a straight or branched chainunsaturated hydrocarbon having the indicated number of carbon atoms andat least one triple bond. Examples of a (C₂-C₈)alkynyl group include,but are not limited to, acetylene, propyne, 1-butyne, 2-butyne,1-pentyne, 2-pentyne, 1-hexyne, 2-hexyne, 3-hexyne, 1-heptyne,2-heptyne, 3-heptyne, 1-octyne, 2-octyne, 3-octyne and 4-octyne. Analkynyl group can be unsubstituted or optionally substituted with one ormore substituents as described herein below.

The term “alkylene” refers to a divalent straight or branched alkylgroup (e.g., an alkyl group attached to two other moieties, oftentimesas a linking group). Examples of a (C₁-C₇)alkylene include —CH₂—,—CH₂CH₂—, —CH₂CH₂CH₂—, —CH₂CH₂CH₂CH₂—, —CH₂CH₂CH₂CH₂CH₂—,—CH₂CH₂CH₂CH₂CH₂CH₂—, and —CH₂CH₂CH₂CH₂CH₂CH₂CH₂—, as well as branchedversions thereof. An alkylene group can be unsubstituted or optionallysubstituted with one or more substituents as described herein below. Forinstance, examples of a (C₃)alkylene-OH include —CH₂CH₂CH₂—OH,—CH₂CH(OH)CH₃, —C(CH₃)₂OH, —CH(OH)CH₂CH₃, and —CH(CH₃)CH₂—OH.

The term “alkoxy” as used herein refers to a straight or branched—O-alkyl group having the indicated number of carbon atoms. For example,a (C₁-C₆)alkoxy group includes, but is not limited to, —O-methyl,—O-ethyl, —O-propyl, —O-isopropyl, —O-butyl, —O-sec-butyl,—O-tert-butyl, —O-pentyl, —O-isopentyl, —O-neopentyl, —O-hexyl,—O-isohexyl, and —O-neohexyl.

The term “aminoalkyl” as used herein refers to a straight or branchedalkyl group (typically one to six carbon atoms) wherein one or more ofthe alkyl group's hydrogen atoms is replaced with an amine of formula—N(R^(a))₂, wherein each occurrence of R^(a) is independently —H or(C₁-C₆)alkyl. Examples of aminoalkyl groups include, but are not limitedto, —CH₂NH₂, —CH₂CH₂NH₂, —CH₂CH₂CH₂NH₂, —CH₂CH₂CH₂CH₂NH₂,—CH₂CH₂CH₂CH₂CH₂NH₂, —CH₂CH₂CH₂CH₂CH₂CH₂NH₂, —CH₂CH₂CH₂N(CH₃)₂,t-butylaminomethyl, isopropylaminomethyl, and the like.

The term “aryl” as used herein refers to a 6- to 14-membered monocyclic,bicyclic, or tricyclic aromatic hydrocarbon ring system. Examples of anaryl group include, but are not limited to, phenyl and naphthyl. An arylgroup can be unsubstituted or optionally substituted with one or moresubstituents as described herein below.

The term “cycloalkyl” as used herein refers to a 3- to 14-memberedsaturated or unsaturated non-aromatic monocyclic, bicyclic, or tricyclichydrocarbon ring system. The bicyclic or tricyclic hydrocarbon ringsystems may be spiro-fused. Included in this class are cycloalkyl groupswhich are fused to a benzene ring. Representative cycloalkyl groupsinclude, but are not limited to, cyclopropyl, cyclobutyl, cyclobutenyl,cyclopentyl, cyclopentenyl, cyclopentadienyl, cyclohexyl, cyclohexenyl,1,3-cyclohexadienyl, cycloheptyl, cycloheptenyl, 1,3-cycloheptadienyl,1,4-cycloheptadienyl, -1,3,5-cycloheptatrienyl, cyclooctyl,cyclooctenyl, 1,3-cyclooctadienyl, 1,4-cyclooctadienyl,-1,3,5-cyclooctatrienyl, spiro[5,4]decane, decahydronaphthalene,octahydronaphthalene, hexahydronaphthalene, octahydroindene,hexahydroindene, tetrahydroinden, decahydrobenzocycloheptene,octahydrobenzocycloheptene, hexahydrobenzocycloheptene,tetrahydrobenzocyclopheptene, dodecahydroheptalene, decahydroheptalene,octahydroheptalene, hexahydroheptalene, and tetrahydroheptalene. Acycloalkyl group can be unsubstituted or optionally substituted with oneor more substituents as described herein below.

The terms “halo”, “halogen”, “halide” and the like as used herein referto —F, —Cl, —Br, or —I.

The term “haloalkyl,” as used herein, refers to a straight or branchedalkyl group wherein one or more of the alkyl group's hydrogen atoms isreplaced with a halogen atom, which can be the same or different.Examples of haloalkyl groups include, but are not limited to,trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl,pentachloroethyl, and 1,1,1-trifluoro-2-bromo-2-chloroethyl.

The term “heteroaryl” as used herein refers to an aromatic heterocyclering of 5 to 14 members, having at least one heteroatom selected fromnitrogen, oxygen and sulfur, and containing at least 1 carbon atom.Heteroaryls may be monocyclic, bicyclic, or tricyclic ring systems.Representative heteroaryls are triazolyl, tetrazolyl, oxadiazolyl,pyridyl, furyl, benzofuranyl, thiophenyl, benzothiophenyl, quinolinyl,pyrrolyl, indolyl, oxazolyl, benzoxazolyl, imidazolyl, benzimidazolyl,thiazolyl, benzothiazolyl, isoxazolyl, pyrazolyl, isothiazolyl,pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, cinnolinyl,phthalazinyl, quinazolinyl, pyrimidyl, azepinyl, oxepinyl, andquinoxalinyl. A heteroaryl group can be unsubstituted or optionallysubstituted with one or more substituents as described herein below.

As used herein, the term “heteroatom” is meant to include oxygen (O),nitrogen (N), and sulfur (S).

The term “heterocycle” or “heterocycloalkyl” as used herein refers to 5-to 14-membered ring systems which are either saturated, unsaturated, oraromatic, and which contain from 1 to 4 heteroatoms independentlyselected from nitrogen, oxygen and sulfur, and wherein the nitrogen andsulfur heteroatoms may be optionally oxidized, and the nitrogenheteroatom may be optionally quaternized. Heterocycles may bemonocyclic, bicyclic, or tricyclic ring systems. The bicyclic ortricyclic ring systems may be spiro-fused. The bicyclic and tricyclicring systems may encompass a heterocycle or heteroaryl fused to abenzene ring. The heterocycle may be attached via any heteroatom orcarbon atom. Heterocycles include heteroaryls as defined above.Representative examples of heterocycles include, but are not limited to,aziridinyl, oxiranyl, thiiranyl, triazolyl, tetrazolyl, azirinyl,diaziridinyl, diazirinyl, oxaziridinyl, azetidinyl, azetidinonyl,oxetanyl, thietanyl, piperidinyl, piperazinyl, morpholinyl, pyrrolyl,oxazinyl, thiazinyl, diazinyl, dioxanyl, triazinyl, tetrazinyl,imidazolyl, tetrazolyl, pyrrolidinyl, isoxazolyl, furanyl, furazanyl,pyridinyl, oxazolyl, benzoxazolyl, benzisoxazolyl, thiazolyl,benzthiazolyl, thiophenyl, pyrazolyl, triazolyl, pyrimidinyl,benzimidazolyl, isoindolyl, indazolyl, benzodiazolyl, benzotriazolyl,benzoxazolyl, benzisoxazolyl, purinyl, indolyl, isoquinolinyl,quinolinyl, and quinazolinyl. A heterocycle group can be unsubstitutedor optionally substituted with one or more substituents as describedherein below.

The term “hydroxyalkyl” as used herein refers to a straight or branchedalkyl group having the indicated number of carbon atoms, wherein one ormore of the alkyl group's hydrogen atoms is replaced with an —OH group.Examples of hydroxyalkyl groups include, but are not limited to, —CH₂OH,—CH₂CH₂OH, —CH₂CH₂CH₂OH, —CH₂CH₂CH₂CH₂OH, —CH₂CH₂CH₂CH₂CH₂OH,—CH₂CH₂CH₂CH₂CH₂CH₂OH, and branched versions thereof.

The term “hydroxyhaloalkyl” as used herein refers to a straight orbranched alkyl group having the indicated number of carbon atoms,wherein one or more of the alkyl group's hydrogen atoms is replaced witha halogen atom, which can be the same or different, and in addition oneor more of the alkyl group's hydrogen atoms is replaced with an —OHgroup. Non-limiting examples of hydroxyhaloalkyl groups include—C(CH₃)(CF₃)OH and —C(CF₃)₂OH.

Substituents for the groups referred to as alkyl, heteroalkyl, alkylene,alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, andheterocycloalkenyl can be a variety of groups including, but not limitedto, —OR^(a), ═O, ═NR^(a), ═N—OR^(a), —NR^(a)R^(b), —SR^(a), -halo,—SiR^(a)R^(b)R^(c), —OC(O)R^(a), —C(O)R^(a), —CO₂R^(a), —CONR^(a)R^(b),—OC(O)NR^(a)R^(b), —NR^(b)C(O)R^(a), —NR^(c)C(O)NR^(a)R^(b),NR^(c)SO₂NR^(a)R^(b), —NR^(b)CO₂R^(a), —NHC(NH₂)═NH, —NR^(a)C(NH₂)═NH,—NHC(NH₂)═NR^(a), —S(O)R^(a), —SO₂R^(a), —SO₂NR^(a)R^(b),—NR^(b)SO₂R^(a), —CN and —NO₂, in a number ranging from zero to three,with those groups having zero, one or two substituents being exemplary.R^(a), R^(b) and R^(c) independently may refer to, e.g., hydrogen,unsubstituted (C₁-C₈)alkyl, unsubstituted hetero(C₁-C₈)alkyl,unsubstituted aryl, and aryl substituted with one to three substituentsselected from, e.g., -halo, unsubstituted alkyl, unsubstituted alkoxy,unsubstituted thioalkoxy, and unsubstituted aryl(C₁-C₄)alkyl. When R^(a)and R^(b) are attached to the same nitrogen atom, they can be combinedwith the nitrogen atom to form, e.g., a 5-, 6- or 7-membered ring. Forexample, —NR^(a)R^(b) is meant to include 1-pyrrolidinyl and4-morpholinyl. An alkyl or heteroalkyl group will have from zero tothree substituents, with those groups having two or fewer substituentsbeing exemplary in the present invention. In some embodiments, an alkylor heteroalkyl radical will be unsubstituted or monosubstituted. Analkyl or heteroalkyl radical can be unsubstituted. From the abovediscussion of substituents, one of skill in the art will understand thatthe term “alkyl” is meant to include groups such as trihaloalkyl (e.g.,—CF₃ and —CH₂CF₃).

Representative examples of substituents for alkyl and heteroalkylradicals are —OR^(a), ═O, —NR^(a)R^(b), —SR^(a), -halo,—SiR^(a)R^(b)R^(c), —OC(O)R^(a), —C(O)R^(a), —CO₂R^(a),—C(O)NR^(a)R^(b), —OC(O)NR^(a)R^(b), —NR^(b)C(O)R^(a), —NR^(b)CO₂R^(a),—NR^(c)SO₂NR^(a)R^(b), —S(O)R^(a), —SO₂R^(a), —SO₂NR^(a)R^(b),—NR^(b)SO₂R^(a), —CN and —NO₂, where R^(a), R^(b) and R^(c) are asdefined above. Exemplary substituents are selected from: —OR^(a), ═O,—NR^(a)R^(b), -halo, —OC(O)R^(a), —CO₂R^(a), —C(O)NR^(a)R^(b),—OC(O)NR^(a)R^(b), —NR^(b)C(O)R^(a), —NR^(b)CO₂R^(a),—NR^(c)SO₂NR^(a)R^(b), —SO₂R^(a), —SO₂NR^(a)R^(b), —NR^(b)SO₂R^(a), —CNand —NO₂.

Similarly, representative examples of substituents for aryl andheteroaryl groups are -halo, —OR^(a), —OC(O)R^(a), —NR^(a)R^(b),—SR^(a), —R^(a), —CN, —NO₂, —CO₂R^(a), —C(O)NR^(a)R^(b), —C(O)R^(a),—OC(O)NR^(a)R^(b), —NR^(b)C(O)R^(a), —NR^(b)CO₂R^(b),—NR^(c)C(O)NR^(a)R^(b), —NR^(c)SO₂NR^(a)R^(b), —NHC(NH₂)═NH,—NR^(a)C(NH₂)═NH, —NH—C(NH₂)═NR^(a), —S(O)R^(a), —SO₂R^(a),—SO₂NR^(a)R^(b), —NR^(b)SO₂R^(a), —N₃, —CH(Ph)₂, perfluoroalkoxy andperfluoro(C₁-C₄)alkyl, in a number ranging from zero to the total numberof open valences on the aromatic ring system. R^(a), R^(b) and R^(c)independently may be, e.g., hydrogen, unsubstituted (C₁-C₈)alkyl,unsubstituted hetero(C₁-C₈)alkyl, unsubstituted aryl, unsubstitutedheteroaryl, unsubstituted aryl(C₁-C₄)alkyl, and unsubstitutedaryloxy(C₁-C₄)alkyl. Typically, an aryl or heteroaryl group will havefrom zero to three substituents, with those groups having two or fewersubstituents being exemplary in the present invention. In one embodimentof the invention, an aryl or heteroaryl group will be unsubstituted ormonosubstituted. In another embodiment, an aryl or heteroaryl group willbe unsubstituted.

Two of the substituents on adjacent atoms of an aryl or heteroaryl ringmay optionally be replaced with a substituent of the formula-T-C(O)—(CH₂)_(q)—U—, wherein T and U are independently —NH—, —O—, —CH₂—or a single bond, and q is an integer from 0 to 2. Alternatively, two ofthe substituents on adjacent atoms of an aryl or heteroaryl ring mayoptionally be replaced with a substituent of the formula-A-(CH₂)_(r)—B—, wherein A and B are independently —CH₂—, —O—, —NH—,—S—, —S(O)—, —S(O)₂—, —S(O)₂NR′— or a single bond, and r is an integerfrom 1 to 3. One of the single bonds of the new ring so formed mayoptionally be replaced with a double bond. Alternatively, two of thesubstituents on adjacent atoms of an aryl or heteroaryl ring mayoptionally be replaced with a substituent of the formula —(CH₂),—X—(CH₂)_(t)—, where s and t independently are integers from 0 to 3, andX is —O—, —NR^(a)—, —S—, —S(O)—, —S(O)₂—, or —S(O)₂NR^(a)—. Thesubstituent R^(a) in —NR^(a)— and —S(O)₂NR^(a)— may be, e.g., hydrogenor unsubstituted (C₁-C₆)alkyl.

It is to be understood that the substituent —CO₂H, as used herein, maybe optionally replaced with bioisosteric replacements such as:

and the like. See, e.g., The Practice of Medicinal Chemistry; Wermuth,C. G., Ed.; Academic Press: New York, 1996; p. 203.

The tricyclic compounds of the present invention can also exist invarious isomeric forms, including stereochemical, configurational,geometric and conformational isomers, as well as exist in varioustautomeric forms, particularly those that differ in the point ofattachment of a hydrogen atom. As used herein, the term “isomer” isintended to encompass all isomeric forms of a tricyclic compound,including tautomeric forms of the compound.

Certain tricyclic compounds may have asymmetric centers and thereforeexist in different enantiomeric or diastereomeric forms. A tricycliccompound can be in the form of an optical isomer or a diastereomer.Accordingly, the invention encompasses tricyclic compounds and theiruses as described herein in the form of their optical isomers,diastereomers and mixtures thereof, including a racemic mixture. Opticalisomers of the tricyclic compounds can be obtained by known techniquessuch as asymmetric synthesis, chiral chromatography, simulated movingbed technology, or via chemical separation of stereoisomers through theemployment of optically active resolving agents.

As used herein and unless otherwise indicated, the term “stereomericallypure” means one stereoisomer of a compound that is substantially free ofother stereoisomers of that compound. For example, a stereomericallypure compound having one chiral center will be substantially free of theopposite enantiomer of the compound. A stereomerically pure compoundhaving two chiral centers will be substantially free of otherdiastereomers of the compound. A typical stereomerically pure compoundcomprises greater than about 80% by weight of one stereoisomer of thecompound and less than about 20% by weight of other stereoisomers of thecompound, or greater than about 90% by weight of one stereoisomer of thecompound and less than about 10% by weight of the other stereoisomers ofthe compound, or greater than about 95% by weight of one stereoisomer ofthe compound and less than about 5% by weight of the other stereoisomersof the compound, or greater than about 97% by weight of one stereoisomerof the compound and less than about 3% by weight of the otherstereoisomers of the compound.

It should be noted that if there is a discrepancy between a depictedstructure and a name given that structure, the depicted structurecontrols. In addition, if the stereochemistry of a structure or aportion of a structure is not indicated with, for example, bold ordashed lines, the structure or portion of the structure is to beinterpreted as encompassing all stereoisomers of it.

A tricyclic compound can be in the form of a pharmaceutically acceptablesalt. Depending on the its structure, the phrase “pharmaceuticallyacceptable salt” as used herein refers to a pharmaceutically acceptableorganic or inorganic acid or base salt of a tricyclic compound.Representative pharmaceutically acceptable salts include, e.g., alkalimetal salts, alkali earth salts, ammonium salts, water-soluble, andwater-insoluble salts, such as the acetate, amsonate(4,4-diaminostilbene-2,2-disulfonate), benzenesulfonate, benzonate,bicarbonate, bisulfate, bitartrate, borate, bromide, butyrate, calcium,calcium edetate, camsylate, carbonate, chloride, citrate, clavulariate,dihydrochloride, edetate, edisylate, estolate, esylate, fiunarate,gluceptate, gluconate, glutamate, glycollylarsanilate,hexafluorophosphate, hexylresorcinate, hydrabamine, hydrobromide,hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate,lactobionate, laurate, malate, maleate, mandelate, mesylate,methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate,N-methylglucamine ammonium salt, 3-hydroxy-2-naphthoate, oleate,oxalate, palmitate, pamoate (1,1-methene-bis-2-hydroxy-3-naphthoate,einbonate), pantothenate, phosphate/diphosphate, picrate,polygalacturonate, propionate, p-toluenesulfonate, salicylate, stearate,subacetate, succinate, sulfate, sulfosaliculate, suramate, tannate,tartrate, teoclate, tosylate, triethiodide, and valerate salts.Furthermore, a pharmaceutically acceptable salt can have more than onecharged atom in its structure. In this instance the pharmaceuticallyacceptable salt can have multiple counterions. Hence, a pharmaceuticallyacceptable salt can have one or more charged atoms and/or one or morecounterions.

As used herein, the term “isolated and purified form” means that whenisolated (e.g., from other components of a synthetic organic chemicalreaction mixture), the isolate contains at least 30%, at least 35%, atleast 40%, at least 45%, at least 50%, at least 55%, at least 60%, atleast 65%, at least 70%, at least 75%, at least 80%, at least 85%, atleast 90%, at least 95%, or at least 98% of a tricyclic compound byweight of the isolate. In one embodiment, the isolate contains at least95% of a tricyclic compound by weight of the isolate.

As used herein, the term “prodrug” means a derivative of a compound thatcan hydrolyze, oxidize, or otherwise react under biological conditions(in vitro or in vivo) to provide an active compound, particularly atricyclic compound. Examples of prodrugs include, but are not limitedto, derivatives and metabolites of a tricyclic compound that includebiohydrolyzable groups such as biohydrolyzable amides, biohydrolyzableesters, biohydrolyzable carbamates, biohydrolyzable carbonates,biohydrolyzable ureides, and biohydrolyzable phosphate analogues (e.g.,monophosphate, diphosphate or triphosphate). For instance, prodrugs ofcompounds with carboxyl functional groups may be the lower alkyl estersof the carboxylic acids. The carboxylate esters are conveniently formedby esterifying any of the carboxylic acid moieties present on themolecule. Prodrugs can typically be prepared using well known methods,such as those described by Burger's Medicinal Chemistry and DrugDiscovery, 6^(th) ed. (Donald J. Abraham ed., 2001, Wiley), and Designand Application of Prodrugs (H. Bundgaard ed., 1985, Harwood AcademicPublishers Gmfh).

As used herein, the terms “treat”, “treating” and “treatment” refer toeradication or amelioration of a disease or symptoms associated with adisease. In certain embodiments, such terms refer to minimizing thespread or worsening of the disease resulting from the administration ofone or more prophylactic or therapeutic agents to a patient with such adisease.

As used herein, the terms “prevent”, “preventing” and “prevention” referto prevention of the onset, recurrence or spread of a disease in apatient resulting from the administration of a prophylactic ortherapeutic agent.

The term “effective amount” as used herein refers to an amount of atricyclic compound or other active ingredient sufficient to provide atherapeutic or prophylactic benefit in the treatment or prevention of adisease or to delay or minimize symptoms associated with a disease.Further, a therapeutically effective amount with respect to a tricycliccompound means that amount of therapeutic agent alone, or in combinationwith other therapies, that provides a therapeutic benefit in thetreatment or prevention of a disease. Used in connection with atricyclic compound, the term can encompass an amount that improvesoverall therapy, reduces or avoids symptoms or causes of disease, orenhances the therapeutic efficacy of or synergies with anothertherapeutic agent.

The terms “modulate”, “modulation” and the like refer to the ability ofa compound to increase or decrease the function, or activity, of atarget (e.g., 11β-HSD1). The term “modulation”, as used herein in itsvarious forms, is intended to encompass inhibition, antagonism, partialantagonism, activation, agonism and/or partial agonism of the function,or activity, of a target (e.g., 11β-HSD1). 11β-HSD1 inhibitors arecompounds that, e.g., bind to, partially or totally block stimulation,decrease, prevent, delay activation, inactivate, desensitize, or downregulate signal transduction. 11β-HSD1 activators are compounds that,e.g., bind to, stimulate, increase, open, activate, facilitate, enhanceactivation, sensitize or up regulate signal transduction.

The ability of a compound to modulate a target (e.g., 11β-HSD1) can bedemonstrated, e.g., in an enzymatic assay or a cell-based assay. Forexample, the inhibition of 11β-HSD1 may decrease cortisol levels in apatient and/or increase cortisone levels in a patient by blocking theconversion of cortisone to cortisol. Alternatively, the inhibition of11β-HSD2 can increase cortisol levels in a patient and/or decreasecortisone levels in a patient by blocking the conversion of cortisol tocortisone.

A “patient” includes an animal (e.g., cow, horse, sheep, pig, chicken,turkey, quail, cat, dog, mouse, rat, rabbit or guinea pig). In oneembodiment, a “patient” includes a mammal such as a non-primate and aprimate (e.g., monkey and human). In another embodiment, a patient is ahuman. In specific embodiments, the patient is a human infant, child,adolescent or adult.

The term “HSD” as used herein refers to hydroxysteroid dehydrogenaseenzymes in general, including, but not limited to,11-beta-hydroxysteroid dehydrogenases (11β-HSDs), 17-beta-hydroxysteroiddehydrogenases (17β-HSDs), 20-alpha-hydroxysteroid dehydrogenases(20α-HSDs), 3-alpha-hydroxysteroid dehydrogenases (3α-HSDs), and allisoforms thereof.

The term “11β-HSD1” as used herein refers to the 11-beta-hydroxysteroiddehydrogenase type 1 enzyme, variant, or isoform thereof. 11β-HSD1variants include proteins substantially homologous to native 11β-HSD1,i.e., proteins having one or more naturally or non-naturally occurringamino acid deletions, insertions or substitutions (e.g., 11β-HSD1derivatives, homologs and fragments). The amino acid sequence of a11β-HSD1 variant is, e.g., at least about 80% identical to a native11β-HSD1, or at least about 90% identical, or at least about 95%identical.

The term “11β-HSD2” as used herein refers to the 11-beta-hydroxysteroiddehydrogenase type 2 enzyme, variant, or isoform thereof 11β-HSD2variants include proteins substantially homologous to native 11β-HSD2,i.e., proteins having one or more naturally or non-naturally occurringamino acid deletions, insertions or substitutions (e.g., 11β-HSD2derivatives, homologs and fragments). The amino acid sequence of a11β-HSD2 variant is, e.g., at least about 80% identical to a native11β-HSD2, or at least about 90% identical, or at least about 95%identical. See Bart et al., J. Med. Chem. 2002, 45:3813-3815.

The term “17β-HSD3” as used herein refers to the 17-beta-hydroxysteroiddehydrogenase type 3 enzyme, variant, or isoform thereof 17β-HSD3variants include proteins substantially homologous to native 17β-HSD3,i.e., proteins having one or more naturally or non-naturally occurringamino acid deletions, insertions or substitutions (e.g., 17β-HSD3derivatives, homologs and fragments). The amino acid sequence of a17β-HSD3 variant is, e.g., at least about 80% identical to a native17β-HSD3, or at least about 90% identical, or at least about 95%identical.

As used herein, the term “HSD-responsive condition or disorder” andrelated terms and phrases refer to a condition or disorder that respondsfavorably to modulation of a hydroxysteroid dehydrogenase enzyme (HSD).Favorable responses to HSD modulation include alleviation or abrogationof the disease and/or its attendant symptoms, inhibition of the disease(i.e., arrest or reduction of the development of the disease, or itsclinical symptoms), and regression of the disease or its clinicalsymptoms. An HSD-responsive condition or disease may be completely orpartially responsive to HSD modulation. An HSD-responsive condition ordisorder may be associated with inappropriate, e.g., less than orgreater than normal, HSD activity and is at least partially responsiveto or affected by HSD modulation (e.g., an HSD inhibitor results in someimprovement in patient well-being in at least some patients).Inappropriate HSD functional activity might arise as the result of HSDexpression in cells which normally do not express HSD, decreased HSDexpression or increased HSD expression. An HSD-responsive condition ordisorder may include condition or disorder mediated by any HSD orisoform thereof.

As used herein, the term “11β-HSD1-responsive condition or disorder” andrelated terms and phrases refer to a condition or disorder that respondsfavorably to modulation of 11β-HSD1 activity. Favorable responses to11β-HSD1 modulation include alleviation or abrogation of the diseaseand/or its attendant symptoms, inhibition of the disease (i.e., arrestor reduction of the development of the disease, or its clinicalsymptoms), and regression of the disease or its clinical symptoms. An11β-HSD1-responsive condition or disease may be completely or partiallyresponsive to 11β-HSD1 modulation. An 11β-HSD1-responsive condition ordisorder may be associated with inappropriate, e.g., less than orgreater than normal, 11β-HSD1 activity and is at least partiallyresponsive to or affected by 11β-HSD1 modulation (e.g., a 11β-HSD1inhibitor results in some improvement in patient well-being in at leastsome patients). Inappropriate 11β-HSD1 functional activity might ariseas the result of 11β-HSD1 expression in cells which normally do notexpress 11β-HSD1, decreased 11β-HSD1 expression or increased 11β-HSD1expression. A 11β-HSD1-responsive condition or disorder may include a11β-HSD1-mediated condition or disorder.

As used herein, the term “11β-HSD2-responsive condition or disorder” andrelated terms and phrases refer to a condition or disorder that respondsfavorably to modulation of 11β-HSD2 activity. Favorable responses to11β-HSD2 modulation include alleviation or abrogation of the diseaseand/or its attendant symptoms, inhibition of the disease (i.e., arrestor reduction of the development of the disease, or its clinicalsymptoms), and regression of the disease or its clinical symptoms. An11β-HSD2-responsive condition or disease may be completely or partiallyresponsive to 11β-HSD2 modulation. An 11β-HSD2-responsive condition ordisorder may be associated with inappropriate, e.g., less than orgreater than normal, 11β-HSD2 activity and is at least partiallyresponsive to or affected by 11β-HSD2 modulation (e.g., a 11β-HSD2inhibitor results in some improvement in patient well-being in at leastsome patients). Inappropriate 11β-HSD2 functional activity might ariseas the result of 11β-HSD2 expression in cells which normally do notexpress 11β-HSD2, decreased 11β-HSD2 expression or increased 11β-HSD2expression. A 11β-HSD2-responsive condition or disorder may include a11β-HSD2-mediated condition or disorder.

As used herein, the term “17β-HSD3-responsive condition or disorder” andrelated terms and phrases refer to a condition or disorder that respondsfavorably to modulation of 17β-HSD3 activity. Favorable responses to17β-HSD3 modulation include alleviation or abrogation of the diseaseand/or its attendant symptoms, inhibition of the disease (i.e., arrestor reduction of the development of the disease, or its clinicalsymptoms), and regression of the disease or its clinical symptoms. An17β-HSD3-responsive condition or disease may be completely or partiallyresponsive to 17β-HSD3 modulation. An 17β-HSD3-responsive condition ordisorder may be associated with inappropriate, e.g., less than orgreater than normal, 17β-HSD3 activity and is at least partiallyresponsive to or affected by 17β-HSD3 modulation (e.g., a 17β-HSD3inhibitor results in some improvement in patient well-being in at leastsome patients). Inappropriate 17β-HSD3 functional activity might ariseas the result of 17β-HSD3 expression in cells which normally do notexpress 17β-HSD3, decreased 17β-HSD3 expression or increased 17β-HSD3expression. A 17β-HSD3-responsive condition or disorder may include a17β-HSD3-mediated condition or disorder.

As used herein, the term “HSD-mediated condition or disorder” andrelated terms and phrases refer to a condition or disorder characterizedby inappropriate, e.g., less than or greater than normal, activity of ahydroxysteroid dehydrogenase (HSD). An HSD-mediated condition ordisorder may be completely or partially characterized by inappropriateHSD activity. However, an HSD-mediated condition or disorder is one inwhich modulation of an HSD results in some effect on the underlyingcondition or disease (e.g., an HSD inhibitor results in some improvementin patient well-being in at least some patients).

As used herein, the term “11β-HSD1-mediated condition or disorder” andrelated terms and phrases refer to a condition or disorder characterizedby inappropriate, e.g., less than or greater than normal, 11β-HSD1activity. A 11β-HSD1-mediated condition or disorder may be completely orpartially characterized by inappropriate 11β-HSD1 activity. However, a11β-HSD1-mediated condition or disorder is one in which modulation of110-HSD1 results in some effect on the underlying condition or disease(e.g., a 11β-HSD1 inhibitor results in some improvement in patientwell-being in at least some patients).

As used herein, the term “11β-HSD2-mediated condition or disorder” andrelated terms and phrases refer to a condition or disorder characterizedby inappropriate, e.g., less than or greater than normal, 11β-HSD2activity. A 11β-HSD2-mediated condition or disorder may be completely orpartially characterized by inappropriate 11β-HSD2 activity. However, a11β-HSD2-mediated condition or disorder is one in which modulation of11β-HSD2 results in some effect on the underlying condition or disease(e.g., a 11β-HSD2 inhibitor results in some improvement in patientwell-being in at least some patients).

As used herein, the term “17β-HSD3-mediated condition or disorder” andrelated terms and phrases refer to a condition or disorder characterizedby inappropriate, e.g., less than or greater than normal, 17β-HSD3activity. A 17β-HSD3-mediated condition or disorder may be completely orpartially characterized by inappropriate 17β-HSD3 activity. However, a17β-HSD3-mediated condition or disorder is one in which modulation of1713-HSD3 results in some effect on the underlying condition or disease(e.g., a 17β-HSD3 inhibitor results in some improvement in patientwell-being in at least some patients).

As used herein, “syndrome X” refers to a collection of abnormalitiesincluding hyperinsulinemia; obesity; elevated levels of triglycerides,uric acid, fibrinogen, small dense LDL particles and plasminogenactivator inhibitor 1 (PAI-1); and decreased levels of HDL cholesterol.Syndrome X is further meant to include metabolic syndrome.

The following abbreviations are used herein and have the indicateddefinitions:

DCM is dichloromethane; DIPEA is diisopropylethylamine; DMAP is4-dimethylaminopyridine; DMEM is Dulbecco's Modified Eagle Medium; EtOAcis ethyl acetate; HPLC is high-performance liquid chromatography; LAH islithium aluminum hydride; MeOH is methanol; MS is mass spectrometry; NMRis nuclear magnetic resonance; PBS is phosphate-buffered saline; RT isroom temperature; SPA is scintillation proximity assay; TBAF istetrabutylammonium fluoride; TBS is tert-butyldimethylsilyl; THF istetrahydrofuran; TLC is thin-layer chromatography; prep TLC ispreparative thin-layer chromatography; and TMS is trimethylsilyl.

It is understood that the word “tricyclic” in the term “tricycliccompound”, when used in reference to compounds of the invention, refersto the tricyclic core of compounds of formula (I). Therefore, the term“tricyclic compound”, when used in reference to compounds of theinvention, may encompass compounds of formula (I) that have one or morecyclic moieties in addition of the tricyclic core.

Compounds of the Invention

The present invention provides compounds of formula (I) as well aspharmaceutically acceptable salts, solvates, stereoisomers or prodrugsthereof, or mixtures thereof, collectively referred to as “the tricycliccompounds” as appropriate:

wherein R¹, R², R³, W, X, Y, Z, m, n, and p are defined below.

In some embodiments, optionally in combination with other embodimentsherein described, each occurrence of R¹ and R² is independentlyhydrogen, halogen, nitro, cyano, (C₁-C₈)alkyl, (C₂-C₈)alkenyl,(C₂-C₈)alkynyl, (C₁-C₈)haloalkyl, (C₁-C₈)hydroxyhaloalkyl,(C₁-C₈)alkyl(C₃-C₇)cycloalkyl, (C₁-C₈)alkyl(C₃-C₇)heterocycloalkyl,(C₁-C₈)alkylaryl, (C₁-C₈)alkylheteroaryl, (C₃-C₇)cycloalkyl,(C₃-C₇)heterocycloalkyl, aryl, heteroaryl, —OR″, —C(O)R′, —C(O)OR′,—OC(O)R′, —OC(O)OR′, —C(O)N(R′)₂, —OC(O)N(R′)₂, —N(R′)₂, —NR′C(O)R′,—NR′C(O)OR″, —NR′C(O)N(R′)₂, —NR′SO₂R″, —SR″, —S(O)R″, —SO₂R″,—S(O)₂OR″, —SO₂N(R′)₂, -L-OR″, -L-C(O)R′, -L-C(O)OR′, -L-OC(O)R′,-L-OC(O)N(R′)₂, -L-N(R′)₂, -L-NR′C(O)OR″, -L-C(O)N(R′)₂, -L-NR′C(O)R″,-L-SR″, -L-S(O)R″, -L-SO₂R″, -L-SO₂N(R′)₂, or -L-NR′SO₂R″.

Each occurrence of R³ is independently null, hydrogen, halogen, nitro,cyano, (C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₁-C₈)haloalkyl,(C₁-C₈)alkyl(C₃-C₇)cycloalkyl, (C₁-C₈)alkyl(C₃-C₇)heterocycloalkyl,(C₁-C₈)alkylaryl, (C₁-C₈)alkylheteroaryl, (C₃-C₇)cycloalkyl,(C₃-C₇)heterocycloalkyl, —OR″, —C(O)R′, —C(O)OR′, —OC(O)R′, —OC(O)OR′,—C(O)N(R′)₂, —OC(O)N(R′)₂, —N(R′)₂, —NR′C(O)R′, —NR′C(O)OR″,—NR′C(O)N(R′)₂, —SR″, —S(O)R″, —SO₂R″, —S(O)₂OR″, —SO₂N(R′)₂, -L-OR″,-L-C(O)R′, -L-C(O)OR′, -L-OC(O)R′, -L-OC(O)N(R′)₂, -L-N(R′)₂,-L-C(O)N(R′)₂, -L-NR′C(O)R″, -L-SR″, -L-S(O)R″, -L-SO₂R″, -L-SO₂N(R′)₂,or -L-NR′SO₂R″.

W is C(R)₂, O, S, NR, NC(O)R′, NC(O)OR′, NC(O)N(R′)₂, or NS(O)₂R′.

X, Y, and Z are independently C, N, O, or S.

Each occurrence of R is independently hydrogen, halogen, cyano,(C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₁-C₈)haloalkyl,(C₁-C₈)hydroxyhaloalkyl, (C₁-C₈)alkyl(C₃-C₇)cycloalkyl,(C₁-C₈)alkyl(C₃-C₇)heterocycloalkyl, (C₁-C₈)alkylaryl,(C₁-C₈)alkylheteroaryl, (C₃-C₇)cycloalkyl, (C₃-C₇)heterocycloalkyl,aryl, heteroaryl, —OR″, —C(O)R′, —C(O)OR′, —OC(O)R′, —OC(O)OR′,—C(O)N(R′)₂, —OC(O)N(R′)₂, —N(R′)₂, —NR′C(O)R′, —NR′C(O)OR″,—NR′C(O)N(R′)₂, —NR′ SO₂R″, —SR″, —S(O)R″, —SO₂R″, —S(O)₂OR″,—SO₂N(R′)₂, -L-OR″, -L-C(O)R′, -L-C(O)OR′, -L-OC(O)R′, -L-OC(O)N(R′)₂,-L-N(R′)₂, -L-NR′C(O)OR″, -L-C(O)N(R′)₂, -L-NR′C(O)R″, -L-SR″,-L-S(O)R″, -L-SO₂R″, -L-SO₂N(R′)₂, or -L-NR′SO₂R″.

Each occurrence of R′ is independently hydrogen, (C₁-C₈)alkyl,(C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₁-C₈)alkoxy(C₁-C₈)alkyl,(C₁-C₈)haloalkyl, (C₁-C₈)hydroxyalkyl, (C₁-C₈)hydroxyhaloalkyl,(C₁-C₈)alkyl(C₃-C₇)cycloalkyl, (C₁-C₈)alkyl(C₃-C₇)heterocycloalkyl,(C₁-C₈)alkylaryl, (C₁-C₈)alkylheteroaryl, (C₃-C₇)cycloalkyl,(C₃-C₇)heterocycloalkyl, aryl, or heteroaryl.

Alternatively, in some embodiments, two R′ groups, when attached to thesame nitrogen atom, can combine with the nitrogen atom to which they areattached to form a heterocyclic or heteroaryl group.

Each occurrence of R″ is independently hydrogen, (C₁-C₈)alkyl,(C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₁-C₈)alkoxy(C₁-C₈)alkyl,(C₁-C₈)haloalkyl, (C₁-C₈)hydroxyalkyl, (C₁-C₈)hydroxyhaloalkyl,(C₁-C₈)alkyl(C₃-C₇)cycloalkyl, (C₁-C₈)alkyl(C₃-C₇)heterocycloalkyl,(C₁-C₈)alkylaryl, (C₁-C₈)alkylheteroaryl, (C₃-C₇)cycloalkyl,(C₃-C₇)heterocycloalkyl, aryl, or heteroaryl.

Any cycloalkyl portion, heterocycloalkyl portion, aryl portion, orheteroaryl portion is optionally substituted with one to four membersselected from the group consisting of hydroxyl, halogen, cyano, nitro,(C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₁-C₈)alkoxy,(C₁-C₈)haloalkyl, (C₁-C₈)hydroxyalkyl, (C₁-C₈)hydroxyhaloalkyl, —OR″,—C(O)R′, —C(O)OR′, —OC(O)R′, —OC(O)OR′, —C(O)N(R′)₂, —OC(O)N(R′)₂,—N(R′)₂, —NR′C(O)R′, —NR′C(O)OR″, —NR′C(O)N(R″)₂, —NR′SO₂R″, —SR″,—S(O)R″, —SO₂R″, —S(O)₂OR″, —SO₂N(R′)₂, -L-OR″, -L-C(O)R′, -L-C(O)OR′,-L-OC(O)R′, -L-OC(O)N(R′)₂, -L-N(R′)₂, -L-NR′C(O)OR″, -L-C(O)N(R′)₂,-L-NR′C(O)R″, -L-SR″, -L-S(O)R″, -L-SO₂R″, -L-SO₂N(R′)₂, and-L-NR′SO₂R″.

L is (C₁-C₈)alkylene.

Variable m is an integer from 1 to 5, n is an integer from 0 to 2, and pis an integer from 0 to 11.

It should be understood that the following compounds are excluded fromthe scope of the present invention:

-   4-cyclohexyl-5-(3-fluorophenyl)-2-methyloxazole

-   4-cyclohexyl-2-ethyl-5-(3-fluorophenyl)oxazole

-   5-(4-chlorophenyl)-4-cyclopentyl-2-[(1S)-1-fluoroethyl]thiazole

-   5-(4-chlorophenyl)-4-cyclohexyl-2-ethylthiazole

-   4-cyclopentyl-2-ethyl-5-(4-ethylphenyl)thiazole

-   5-(3-chlorophenyl)-4-cyclopentyl-2-ethylthiazole

-   4-cyclopentyl-2-ethyl-5-(3-methylphenyl)thiazole

-   5-(2-chlorophenyl)-4-cyclopentyl-2-ethylthiazole

-   4-cyclopentyl-2-ethyl-5-(2-methylphenyl)thiazole

-   4-cyclohexyl-5-(3-fluorophenyl)-2-methyloxazole

-   3-[4-(4-fluorophenyl)-2-methyl-5-thiazolyl]-1-pyrrolidinecarboxylic    acid, ethyl ester

-   4-(4-fluorophenyl)-2-methyl-5-(3-pyrrolidinyl)thiazole

-   1-(4-fluorophenyl)-4-[3-[4-(4-fluorophenyl)-2-methyl-5-thiazolyl]-1-pyrrolidinyl]-1-butanone

-   4-(4-fluorophenyl)-5-[1-[3-[2-(4-fluorophenyl)-1,3-dioxolan-2-yl]propyl]-3-pyrrolidinyl]-2-methylthiazole

-   4-cyclohexyl-5-(3-fluorophenyl)-2-methyloxazole

-   4-[5-cyclohexyl-2-(methylthio)-4-thiazolyl]-2,6-bis(1,1-dimethylethyl)phenol

In one embodiment, optionally in combination with other embodimentsherein described, at least one occurrence of R′ is other than hydrogen.

In another embodiment, optionally in combination with other embodimentsherein described, no occurrence of R¹ is —SO₂NH₂, —SO₂NH-alkyl, or—SO₂-alkyl.

In yet another embodiment, optionally in combination with otherembodiments herein described, no occurrence of R² is —C(O)N(R′)₂,hydroxyalkyl, alkoxyalkyl, or —CO₂H.

In a further embodiment, optionally in combination with otherembodiments herein described, no occurrence of R³ is hydroxyl,hydroxyalkyl, alkoxyalkyl, —NH₂, —NH-alkyl, aminoalkyl, —C(O)O-alkyl,—C(O)-alkyl, or -L-OC(O)-alkyl.

In still another embodiment, optionally in combination with otherembodiments herein described, when X is S and Y is N, then no occurrenceof R¹ is:

-   -   cyano or nitro;    -   —OR″, —SR″, hydroxyalkyl, or —OC(O)-alkyl;    -   —NH₂, —NHR′, —N(alkyl)₂, —NR′C(O)R′, —NR′C(O)OR″, or        —NR′C(O)N(R′)₂; or    -   —C(O)-alkyl, —C(O)-aryl, —CO₂H, —C(O)O-alkyl, —C(O)N(R′)₂, or        -L-C(O)R′.

In another embodiment, optionally in combination with other embodimentsherein described, m is 1, 2 or 3, and p is 0, 1 or 2.

In still another embodiment, optionally in combination with otherembodiments herein described, m is 1 or 2, and p is 0 or 1.

In some embodiments, each occurrence of R′ and R² is independentlyhydrogen, hydroxyl, halogen, nitro, cyano, (C₁-C₈)alkyl, (C₁-C₈)alkoxy,(C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₁-C₈)haloalkyl, (C₁-C₈)hydroxyalkyl,(C₁-C₈)hydroxyhaloalkyl, (C₁-C₈)alkoxy(C₁-C₈)alkyl,(C₁-C₈)alkyl(C₃-C₇)cycloalkyl, (C₁-C₈)alkyl(C₃-C₇)heterocycloalkyl,(C₁-C₈)alkylaryl, (C₁-C₈)alkylheteroaryl, (C₃-C₇)cycloalkyl,(C₃-C₇)heterocycloalkyl, aryl, heteroaryl, or —C(O)R′.

In other embodiments, each occurrence of R³ is independently null,hydrogen, halogen, cyano, (C₁-C₈)alkyl, (C₁-C₈)alkoxy, (C₂-C₈)alkenyl,(C₂-C₈)alkynyl, (C₁-C₈)haloalkyl, (C₁-C₈)alkoxy(C₁-C₈)alkyl,(C₁-C₈)alkyl(C₃-C₇)cycloalkyl, (C₁-C₈)alkyl(C₃-C₇)heterocycloalkyl,(C₁-C₈)alkylaryl, (C₁-C₈)alkylheteroaryl, (C₃-C₇)cycloalkyl, or(C₃-C₇)heterocycloalkyl.

In yet another embodiment, optionally in combination with otherembodiments herein described, n is 0 or 1, and p is 0.

In some embodiments, each occurrence of R¹ is independently hydrogen,hydroxyl, halogen, (C₁-C₈)alkyl, (C₁-C₈)alkoxy, (C₁-C₈)haloalkyl,(C₁-C₈)hydroxyalkyl, (C₁-C₈)hydroxyhaloalkyl, (C₁-C₈)alkoxy(C₁-C₈)alkyl,(C₃-C₇)cycloalkyl, (C₃-C₇)heterocycloalkyl, aryl, heteroaryl, or—C(O)R′.

In yet other embodiments, each occurrence of R³ is independently null,hydrogen, halogen, (C₁-C₈)alkyl, (C₁-C₈)alkoxy, (C₁-C₈)haloalkyl,(C₁-C₈)alkoxy(C₁-C₈)alkyl, (C₃-C₇)cycloalkyl, or(C₃-C₇)heterocycloalkyl.

In another embodiment, W is C(R)₂, O, NR, NC(O)R′, or NS(O)₂R′.

In one embodiment, optionally in combination with other embodimentsherein described, X is O, Z is N, and Y is C.

In another embodiment, optionally in combination with other embodimentsherein described, X is N, Z is O, and Y is C.

In yet another embodiment, optionally in combination with otherembodiments herein described, X is C, Z is N, and Y is O.

In still another embodiment, optionally in combination with otherembodiments herein described, X is C, Z is O, and Y is N.

In yet another embodiment, optionally in combination with otherembodiments herein described, X is N, Z is N, and Y is C. In oneembodiment, R³ attached to X is null and R³ attached to Z is other thannull. In another embodiment, R³ attached to Z is null and R³ attached toX is other than null.

In a further embodiment, optionally in combination with otherembodiments herein described, X is C, Z is N, and Y is N. In oneembodiment, R³ attached to Z is null and R³ attached to Y is other thannull. In another embodiment, R³ attached to Y is null and R³ attached toZ is other than null.

In still another embodiment, optionally in combination with otherembodiments herein described, X is O, Z is C, and Y is N.

In yet another embodiment, optionally in combination with otherembodiments herein described, X is N, Z is C, and Y is O.

In a further embodiment, optionally in combination with otherembodiments herein described, X is S, Z is C, and Y is N.

In another embodiment, optionally in combination with other embodimentsherein described, X is N, Z is C, and Y is S.

In one embodiment, optionally in combination with other embodimentsherein described, X is O, Z is N, Y is C, m is 2, n is 1, p is 0, and Wis C(R)₂.

In another embodiment, optionally in combination with other embodimentsherein described, X is O, Z is N, Y is C, m is 1, n is 1, p is 0, and Wis C(R)₂, wherein R′ is hydroxyhaloalkyl and at least one occurrence ofR is aryl.

Compounds of formula (I) can have asymmetric centers and therefore existin different enantiomeric or diastereomeric forms. The present inventionrelates to the use of all optical isomers and stereoisomers of compoundsof formula (I), and mixtures thereof, and to all pharmaceuticalcompositions and methods of treatment that may employ or contain them.

It should be noted that racemates, racemic mixtures, and stereoisomers,particularly diastereomeric mixtures or diastereomerically purecompounds and enantiomers or enantiomerically pure compounds of theabove, are all encompassed by the present invention.

Specific examples of compounds of formula (I) are provided below inTable 1:

TABLE 1 Examples of compounds of formula (I)

The present invention also provides tricyclic compounds of formula (I)that are in isolated and purified form.

The present invention further provides pharmaceutical compositionscomprising a therapeutically effective amount of a tricyclic compound offormula (I) and a pharmaceutically acceptable vehicle, carrier, diluentor excipient.

In one embodiment, the pharmaceutical compositions comprise a tricycliccompound selected from Table 1 above.

Moreover, the present invention provides pharmaceutical compositionscomprising a therapeutically effective amount of a tricyclic compound offormula (I) and one or more additional therapeutic agents.

In an embodiment, the pharmaceutical compositions comprise one or moreadditional therapeutic agents that are useful for treating a conditionor disorder selected from the group consisting of diabetes, syndrome X,obesity, polycystic ovarian disease, an eating disorder,craniopharyngioma, Prader-Willi syndrome, Frohlich's syndrome,hyperlipidemia, dyslipidemia, hypercholesterolemia,hypertriglyceridemia, low HDL levels, high HDL levels, hyperglycemia,insulin resistance, hyperinsulinemia, Cushing's syndrome, hypertension,atherosclerosis, vascular restenosis, retinopathy, nephropathy,neurodegenerative disease, neuropathy, muscle wasting, a cognitivedisorder, dementia, depression, psoriasis, glaucoma, osteoporosis, aviral infection, an inflammatory disorder, and an immune disorder.

Further, the present invention provides a method for treating acondition or disorder selected from the group consisting of diabetes,syndrome X, obesity, polycystic ovarian disease, an eating disorder,craniopharyngioma, Prader-Willi syndrome, Frohlich's syndrome,hyperlipidemia, dyslipidemia, hypercholesterolemia,hypertriglyceridemia, low HDL levels, high HDL levels, hyperglycemia,insulin resistance, hyperinsulinemia, Cushing's syndrome, hypertension,atherosclerosis, vascular restenosis, retinopathy, nephropathy,neurodegenerative disease, neuropathy, muscle wasting, a cognitivedisorder, dementia, depression, psoriasis, glaucoma, osteoporosis, aviral infection, an inflammatory disorder, and an immune disorder,comprising administering to a patient in need thereof a therapeuticallyeffective amount of a tricyclic compound of formula (I).

In one embodiment, the tricyclic compound is selected from Table Iabove.

In an embodiment, the invention provides a method for treatinginsulin-dependent diabetes mellitus, comprising administering to apatient in need thereof a therapeutically effective amount of atricyclic compound of formula (I).

In another embodiment, the invention provides a method for treatingnon-insulin-dependent diabetes mellitus, comprising administering to apatient in need thereof a therapeutically effective amount of atricyclic compound of formula (I).

In yet another embodiment, the invention provides a method for treatinginsulin resistance, comprising administering to a patient in needthereof a therapeutically effective amount of a tricyclic compound offormula (I).

In a further embodiment, the invention provides a method for treatingobesity, comprising administering to a patient in need thereof atherapeutically effective amount of a tricyclic compound of formula (I).

The invention also provides a method for modulating cortisol production,comprising administering to a patient in need thereof a therapeuticallyeffective amount of a tricyclic compound of formula (I).

Moreover, the invention provides a method for modulating hepatic glucoseproduction, comprising administering to a patient in need thereof atherapeutically effective amount of a tricyclic compound of formula (I).

Furthermore, the invention provides a method for modulating hypothalamicfunction, comprising administering to a patient in need thereof atherapeutically effective amount of a tricyclic compound of formula (I).

The present invention also provides a method for treating ahydroxysteroid dehydrogenase-mediated condition or disorder, comprisingadministering to a patient in need thereof a therapeutically effectiveamount of a tricyclic compound of formula (I).

Furthermore, the invention provides a method for treating a condition ordisorder responsive to modulation of a hydroxysteroid dehydrogenase,comprising administering to a patient in need thereof a therapeuticallyeffective amount of a compound of formula (I).

In one embodiment, the hydroxysteroid dehydrogenase is 11β-HSD1.

The present invention also provides a method for modulating ahydroxysteroid dehydrogenase, comprising administering to a patient inneed thereof a therapeutically effective amount of a tricyclic compoundof formula (I).

Further, the invention provides a method for modulating the function ofa hydroxysteroid dehydrogenase in a cell. In one embodiment, the cell iscontacted with a tricyclic compound of formula (I). In anotherembodiment, a therapeutically effective amount of a tricyclic compoundof formula (I) is administered to a patient in need of such modulation.In a further embodiment, the tricyclic compound inhibits thehydroxysteroid dehydrogenase.

In one embodiment, the hydroxysteroid dehydrogenase is 11β-HSD1.

In an embodiment, the invention provides a method for treating an11β-HSD1-mediated condition or disorder, comprising administering to apatient in need thereof a therapeutically effective amount of atricyclic compound of formula (I).

In another embodiment, the invention provides a method for treating acondition or disorder responsive to modulation of 11β-HSD1, comprisingadministering to a patient in need thereof a therapeutically effectiveamount of a tricyclic compound of formula (I).

In yet another embodiment, the invention provides a method formodulating 11β-HSD1, comprising administering to a patient in needthereof a therapeutically effective amount of a tricyclic compound offormula (I).

In a further embodiment, the invention provides a method for modulatingthe function of 11β-HSD1 in a cell, comprising administering to apatient in need thereof a therapeutically effective amount of atricyclic compound of formula (I).

In an embodiment, the invention provides a method for treating an11β-HSD2-mediated condition or disorder, comprising administering to apatient in need thereof a therapeutically effective amount of atricyclic compound of formula (I).

In another embodiment, the invention provides a method for treating acondition or disorder responsive to modulation of 11β-HSD2, comprisingadministering to a patient in need thereof a therapeutically effectiveamount of a tricyclic compound of formula (I).

In yet another embodiment, the invention provides a method formodulating 11β-HSD2, comprising administering to a patient in needthereof a therapeutically effective amount of a tricyclic compound offormula (I).

In still another embodiment, the invention provides a method formodulating the function of 11β-HSD2 in a cell, comprising administeringto a patient in need thereof a therapeutically effective amount of atricyclic compound of formula (I).

In an embodiment, the invention provides a method for treating an17β-HSD3-mediated condition or disorder, comprising administering to apatient in need thereof a therapeutically effective amount of atricyclic compound of formula (I).

In another embodiment, the invention provides a method for treating acondition or disorder responsive to modulation of 17β-HSD3, comprisingadministering to a patient in need thereof a therapeutically effectiveamount of a tricyclic compound of formula (I).

In a further embodiment, the invention provides a method for modulating17β-HSD3, comprising administering to a patient in need thereof atherapeutically effective amount of a tricyclic compound of formula (I).

In yet another embodiment, the invention provides a method formodulating the function of 17β-HSD3 in a cell, comprising administeringto a patient in need thereof a therapeutically effective amount of atricyclic compound of formula (I).

The present invention also relates to the use of a compound of formula(I) according to any one of the above embodiments in the preparation ofa medicament. In one embodiment, the medicament comprises a compound offormula (I) according to any one of the above embodiments and apharmaceutically acceptable vehicle, carrier, excipient, or diluent.

Further, the present invention relates to the use of a compound offormula (I) according to any one of the above embodiments in thepreparation of a medicament for treating a hydroxysteroiddehydrogenase-mediated condition or disorder, the medicament comprisingthe compound of formula (I) and a pharmaceutically acceptable vehicle,carrier, excipient, or diluent.

In an embodiment, the invention relates to the use of a compound offormula (I) according to any one of the above embodiments in thepreparation of a medicament for treating a condition or disordermediated by 11β-HSD1, 11β-HSD2 or 17β-HSD3, the medicament comprisingthe compound of formula (I) and a pharmaceutically acceptable carrier.

Moreover, the present invention relates to the use of a compound offormula (I) according to any one of the above embodiments in thepreparation of a medicament for treating a condition or disorderresponsive to modulation of a hydroxysteroid dehydrogenase, themedicament comprising the compound of formula (I) and a pharmaceuticallyacceptable vehicle, carrier, excipient, or diluent.

In an embodiment, the invention relates to the use of a compound offormula (I) according to any one of the above embodiments in thepreparation of a medicament for treating a condition or disorderresponsive to modulation of 11β-HSD1, 11β-HSD2 or 17β-HSD3, themedicament comprising the compound of formula (I) and a pharmaceuticallyacceptable carrier.

Furthermore, the present invention relates to the use of a compound offormula (I) according to any one of the above embodiments in thepreparation of a medicament for the treatment of diabetes, syndrome X,obesity, polycystic ovarian disease, an eating disorder,craniopharyngioma, Prader-Willi syndrome, Frohlich's syndrome,hyperlipidemia, dyslipidemia, hypercholesterolemia,hypertriglyceridemia, low HDL levels, high HDL levels, hyperglycemia,insulin resistance, hyperinsulinemia, Cushing's syndrome, hypertension,atherosclerosis, vascular restenosis, retinopathy, nephropathy,neurodegenerative disease, neuropathy, muscle wasting, a cognitivedisorder, dementia, depression, psoriasis, glaucoma, osteoporosis, aviral infection, an inflammatory disorder, or an immune disorder, themedicament comprising the compound of formula (I) and a pharmaceuticallyacceptable vehicle, carrier, excipient, or diluent.

One embodiment of the invention relates to the use of a compound offormula (I) according to any one of the above embodiments in thepreparation of a medicament for the treatment of diabetes, themedicament comprising the compound of formula (I) and a pharmaceuticallyacceptable carrier.

Another embodiment of the invention relates to the use of a compound offormula (I) according to any one of the above embodiments in thepreparation of a medicament for the treatment of insulin-dependentdiabetes mellitus, the medicament comprising the compound of formula (I)and a pharmaceutically acceptable carrier.

A further embodiment of the invention relates to the use of a compoundof formula (I) according to any one of the above embodiments in thepreparation of a medicament for the treatment of non-insulin-dependentdiabetes mellitus, the medicament comprising the compound of formula (I)and a pharmaceutically acceptable carrier.

Yet another embodiment of the invention relates to the use of a compoundof formula (I) according to any one of the above embodiments in thepreparation of a medicament for the treatment of insulin resistance, themedicament comprising the compound of formula (I) and a pharmaceuticallyacceptable carrier.

An embodiment of the invention relates to the use of a compound offormula (I) according to any one of the above embodiments in thepreparation of a medicament for the treatment of obesity, the medicamentcomprising the compound of formula (I) and a pharmaceutically acceptablecarrier.

Another embodiment of the invention relates to the use of a compound offormula (I) according to any one of the above embodiments in thepreparation of a medicament for modulating cortisol production, themedicament comprising the compound of formula (I) and a pharmaceuticallyacceptable carrier.

Yet another embodiment of the invention relates to the use of a compoundof formula (I) according to any one of the above embodiments in thepreparation of a medicament for modulating hepatic glucose production,the medicament comprising the compound of formula (I) and apharmaceutically acceptable carrier.

A further embodiment of the invention relates to the use of a compoundof formula (I) according to any one of the above embodiments in thepreparation of a medicament for modulating hypothalamic function, themedicament comprising the compound of formula (I) and a pharmaceuticallyacceptable carrier.

One embodiment of the invention relates to the use of a compound offormula (I) according to any one of the above embodiments in thepreparation of a medicament for modulating a hydroxysteroiddehydrogenase, the medicament comprising the compound of formula (I) anda pharmaceutically acceptable carrier.

Another embodiment of the invention relates to the use of a compound offormula (I) according to any one of the above embodiments in thepreparation of a medicament for modulating 11β-HSD1, 11β-HSD2 or17β-HSD3, the medicament comprising the compound of formula (I) and apharmaceutically acceptable carrier.

Yet another embodiment of the invention relates to the use of a compoundof formula (I) according to any one of the above embodiments in thepreparation of a medicament for modulating the function of ahydroxysteroid dehydrogenase, the medicament comprising the compound offormula (I) and a pharmaceutically acceptable carrier.

Still another embodiment of the invention relates to the use of acompound of formula (I) according to any one of the above embodiments inthe preparation of a medicament for modulating the function of 11β-HSD1,111β-HSD2 or 17β-HSD3, the medicament comprising the compound of formula(I) and a pharmaceutically acceptable carrier.

A further embodiment of the invention relates to the use of a compoundof formula (I) according to any one of the above embodiments in thepreparation of a medicament for the inhibition of a hydroxysteroiddehydrogenase, the medicament comprising the compound of formula (I) anda pharmaceutically acceptable carrier.

Yet another embodiment of the invention relates to the use of a compoundof formula (I) according to any one of the above embodiments in thepreparation of a medicament for the inhibition of 11β-HSD1, 11β-HSD2 or17β-HSD3, the medicament comprising the compound of formula (I) and apharmaceutically acceptable carrier.

The present invention also relates to the manufacture of a medicamentcomprising a compound of formula (I) according to any one of the aboveembodiments.

Further, the present invention relates to a method of manufacturing amedicament comprising a compound of formula (I) according to any one ofthe above embodiments, the method comprising combining the compound offormula (I) with a pharmaceutically acceptable vehicle, carrier,excipient, or diluent to form the medicament.

In one embodiment, the invention relates to a method of manufacturing amedicament for treating a hydroxysteroid dehydrogenase-mediatedcondition or disorder, the method comprising combining a compound offormula (I) according to any one of the above embodiments with apharmaceutically acceptable carrier to form the medicament.

In another embodiment, the invention relates to a method ofmanufacturing a medicament for treating a condition or disorderresponsive to modulation of a hydroxysteroid dehydrogenase, the methodcomprising combining a compound of formula (I) according to any one ofthe above embodiments with a pharmaceutically acceptable carrier to formthe medicament.

In a further embodiment, the invention relates to a method ofmanufacturing a medicament for the treatment of diabetes, syndrome X,obesity, polycystic ovarian disease, an eating disorder,craniopharyngioma, Prader-Willi syndrome, Frohlich's syndrome,hyperlipidemia, dyslipidemia, hypercholesterolemia,hypertriglyceridemia, low HDL levels, high HDL levels, hyperglycemia,insulin resistance, hyperinsulinemia, Cushing's syndrome, hypertension,atherosclerosis, vascular restenosis, retinopathy, nephropathy,neurodegenerative disease, neuropathy, muscle wasting, a cognitivedisorder, dementia, depression, psoriasis, glaucoma, osteoporosis, aviral infection, an inflammatory disorder, or an immune disorder, themethod comprising combining a compound of formula (I) according to anyone of the above embodiments with a pharmaceutically acceptable carrierto form the medicament.

In yet another embodiment, the invention relates to a method ofmanufacturing a medicament for modulating a hydroxysteroiddehydrogenase, the method comprising combining a compound of formula (I)according to any one of the above embodiments with a pharmaceuticallyacceptable carrier to form the medicament.

In still another embodiment, the invention relates to a method ofmanufacturing a medicament for modulating the function of ahydroxysteroid dehydrogenase, the method comprising combining a compoundof formula (I) according to any one of the above embodiments with apharmaceutically acceptable carrier to form the medicament.

In a further embodiment, the invention relates to a method ofmanufacturing a medicament for the inhibition of a hydroxysteroiddehydrogenase, the method comprising combining a compound of formula (I)according to any one of the above embodiments with a pharmaceuticallyacceptable carrier to form the medicament.

Pharmaceutical Compositions

Pharmaceutical compositions and single unit dosage forms comprising atricyclic compound, or a pharmaceutically acceptable stereoisomer,prodrug, salt, solvate, hydrate, or clathrate thereof, are alsoencompassed by the invention. Individual dosage forms of the inventionmay be suitable for oral, mucosal (including sublingual, buccal, rectal,nasal, or vaginal), parenteral (including subcutaneous, intramuscular,bolus injection, intraarterial, or intravenous), transdermal, or topicaladministration.

Single unit dosage forms of the invention are suitable for oral, mucosal(e.g., nasal, sublingual, vaginal, buccal, or rectal), parenteral (e.g.,subcutaneous, intravenous, bolus injection, intramuscular, orintraarterial), or transdermal administration to a patient. Examples ofdosage forms include, but are not limited to: tablets; caplets;capsules, such as soft elastic gelatin capsules; cachets; troches;lozenges; dispersions; suppositories; ointments; cataplasms (poultices);pastes; powders; dressings; creams; plasters; solutions; patches;aerosols (e.g., nasal sprays or inhalers); gels; liquid dosage formssuitable for oral or mucosal administration to a patient, includingsuspensions (e.g., aqueous or non-aqueous liquid suspensions,oil-in-water emulsions, or water-in-oil liquid emulsions), solutions,and elixirs; liquid dosage forms suitable for parenteral administrationto a patient; and sterile solids (e.g., crystalline or amorphous solids)that can be reconstituted to provide liquid dosage forms suitable forparenteral administration to a patient.

The composition, shape, and type of dosage forms of the invention willtypically vary depending on their use. For example, a dosage form usedin the acute treatment of inflammation or a related disease may containlarger amounts of one or more of the active ingredients it comprisesthan a dosage form used in the chronic treatment of the same disease.Similarly, a parenteral dosage form may contain smaller amounts of oneor more of the active ingredients it comprises than an oral dosage formused to treat the same disease or disorder. These and other ways inwhich specific dosage forms encompassed by this invention will vary fromone another will be readily apparent to those skilled in the art. See,e.g., Remington's Pharmaceutical Sciences, 18th ed., Mack Publishing,Easton, Pa. (1990).

Typical pharmaceutical compositions and dosage forms comprise one ormore carriers, excipients or diluents. Suitable excipients are wellknown to those skilled in the art of pharmacy, and non-limiting examplesof suitable excipients are provided herein. Whether a particularexcipient is suitable for incorporation into a pharmaceuticalcomposition or dosage form depends on a variety of factors well known inthe art including, but not limited to, the way in which the dosage formwill be administered to a patient. For example, oral dosage forms suchas tablets may contain excipients not suited for use in parenteraldosage forms. The suitability of a particular excipient may also dependon the specific active ingredients in the dosage form.

This invention further encompasses anhydrous (e.g., <1% water)pharmaceutical compositions and dosage forms comprising activeingredients, since water can facilitate the degradation of somecompounds. For example, the addition of water (e.g., 5%) is widelyaccepted in the pharmaceutical arts as a means of simulating long-termstorage in order to determine characteristics such as shelf-life or thestability of formulations over time. See, e.g., Jens T. Carstensen, DrugStability: Principles & Practice, 2d. Ed., Marcel Dekker, NY, N.Y.,1995, pp. 379-80. In effect, water and heat accelerate the decompositionof some compounds. Thus, the effect of water on a formulation can be ofgreat significance since moisture and/or humidity are commonlyencountered during manufacture, handling, packaging, storage, shipment,and use of formulations.

Anhydrous pharmaceutical compositions and dosage forms of the inventioncan be prepared using anhydrous or low moisture containing ingredientsand low moisture or low humidity conditions. Pharmaceutical compositionsand dosage forms that comprise lactose and at least one activeingredient that comprises a primary or secondary amine can be anhydrousif substantial contact with moisture and/or humidity duringmanufacturing, packaging, and/or storage is expected.

An anhydrous pharmaceutical composition should be prepared and storedsuch that its anhydrous nature is maintained. Accordingly, anhydrouscompositions can be packaged using materials known to prevent exposureto water such that they can be included in suitable formulary kits.Examples of suitable packaging include, but are not limited to,hermetically sealed foils, plastics, unit dose containers (e.g., vials),blister packs, and strip packs.

The invention further encompasses pharmaceutical compositions and dosageforms that comprise one or more compounds that reduce the rate by whichan active ingredient will decompose. Such compounds, which are referredto herein as “stabilizers,” include, but are not limited to,antioxidants such as ascorbic acid, pH buffers, or salt buffers.

The tricyclic compounds can be administered to a mammal (e.g., human,mouse, rat, rabbit, dog, cat, bovine, pig, monkey) as 11β-HSD1modulators, prophylactic or therapeutic drugs of diabetes, prophylacticor therapeutic drugs of diabetic complications (e.g., retinopathy,nephropathy, neuropathy, cardiac infarction, and cerebral infarctionbased on arteriosclerosis), prophylactic or therapeutic drugs ofhyperlipemia, prophylactic or therapeutic drugs of obesity,neurodegenerative diseases and the like, or prophylactic or therapeuticdrugs of diseases mediated by 11β-HSD1.

The tricyclic compounds can be administered to a mammal concurrentlywith one or more additional therapeutic agents for the treatment of adisease, such as diabetes or obesity, with the aim of the prophylaxis ortreatment of a disease. As such, the tricyclic compounds of the presentinvention can be administered in combination with other therapeuticagents for the treatment or prevention of numerous diseases, including,but not limited to, diabetes and obesity.

Depending on the disease to be treated and the patient's condition, thecompounds of the invention may be administered by oral, parenteral(e.g., intramuscular, intraperitoneal, intravenous, ICV, intracisternalinjection or infusion, subcutaneous injection or implant), inhalation,nasal, vaginal, rectal, sublingual, or topical (e.g., transdermal,local) routes of administration and may be formulated, alone ortogether, in suitable dosage unit formulations containing conventionalnon-toxic pharmaceutically acceptable carriers, adjuvants and vehiclesappropriate for each route of administration. The invention alsocontemplates administration of the compounds of the invention in a depotformulation, in which the active ingredient is released over a definedtime period.

In the case of a combined administration, the tricyclic compounds may beadministered simultaneously with one or more additional therapeuticagents that are useful for the treatment or prevention of diabetes,obesity or other disease, or may be administered at a time prior to orsubsequent to other therapeutic agent(s). In the case of combinedadministration, a pharmaceutical composition containing the tricycliccompound and one or more additional therapeutic agents can beadministered. Alternatively, a pharmaceutical composition containing thetricyclic compound and a pharmaceutical composition containing one ormore additional therapeutic agents may be administered separately. Theadministration routes of respective pharmaceutical compositions may bethe same or different.

In the case of a combined administration, the tricyclic compounds may beadministered at a dose of 50 mg to 800 mg per administration, which maybe given once to several times a day or less frequently (e.g., onceweekly). In addition, the compound may be administered at a smallerdose. The combined pharmaceutical agent can be administered at a dosegenerally employed for the prophylaxis or treatment of diabetes orobesity or at a smaller dose than that.

Like the amounts and types of excipients, the amounts and specific typesof active ingredients in a dosage form may differ depending on factorssuch as, but not limited to, the route by which they are to beadministered to patients. However, typical dosage forms of the inventioncomprise a tricyclic compound, or a pharmaceutically acceptable salt,solvate, clathrate, hydrate, polymorph or prodrug thereof. In thetreatment or prevention of diabetes, obesity, glaucoma, osteoporosis,cognitive disorders, immune disorders, depression or other conditions ordisorders associated with the modulation of an hydroxysteroiddehydrogenase, an appropriate dosage level will generally be from about0.001 to about 100 mg per kg patient body weight per day which can beadministered in single or multiple doses. An exemplary dosage level willbe from about 0.01 to about 25 mg/kg per day or about 0.05 to about 10mg/kg per day. In other embodiments, a suitable dosage level may be fromabout 0.01 to about 25 mg/kg per day, about 0.05 to about 10 mg/kg perday, or about 0.1 to about 5 mg/kg per day. Within this range the dosagemay be from about 0.005 to about 0.05, from about 0.05 to about 0.5, orfrom about 0.5 to about 5.0 mg/kg per day, which lie within the range offrom about 0.1 mg to about 2000 mg per day, and which may be given as asingle once-a-day dose in the morning or as divided doses throughout theday taken with food. In one embodiment, the daily dose is administeredtwice daily in equally divided doses. A daily dose range can be fromabout 5 mg to about 500 mg per day, or between about 10 mg and about 300mg per day. In managing the patient, the therapy can be initiated at alower dose, perhaps from about 1 mg to about 25 mg, and increased ifnecessary up to from about 200 mg to about 2000 mg per day as either asingle dose or divided doses, depending on the patient's globalresponse.

For multidrug therapy, the weight ratio of the compound of the inventionto the second active ingredient may be varied and will depend upon theeffective dose of each ingredient. Generally, an effective dose of eachwill be used. Thus, for example, when a compound of the invention iscombined with an NSAID, the weight ratio of the compound of theinvention to the NSAID will generally range from about 1000:1 to about1:1000, such as about 200:1 to about 1:200. Combinations of a compoundof the invention and other active ingredients generally will also bewithin the aforementioned range, but in each case, an effective dose ofeach active ingredient should be used.

It will be understood, however, that the specific dose level andfrequency of dosage for any particular patient may be varied and willdepend upon a variety of factors including: the activity of the specificcompound employed; the metabolic stability and length of action of thatcompound; the age, body weight, general health, sex, and diet of thepatient; mode and time of administration; rate of excretion; drugcombination; the severity of the particular condition, and the hostundergoing therapy.

Oral Dosage Forms

Pharmaceutical compositions of the invention that are suitable for oraladministration can be presented as discrete dosage forms, such as, butare not limited to, tablets (e.g., chewable tablets), caplets, capsules,and liquids (e.g., flavored syrups). Such dosage forms containpredetermined amounts of active ingredients, and may be prepared bymethods of pharmacy well known to those skilled in the art. Seegenerally, Remington's Pharmaceutical Sciences, 18th ed., MackPublishing, Easton, Pa. (1990).

Typical oral dosage forms of the invention are prepared by combining theactive ingredient(s) in an intimate admixture with at least oneexcipient according to conventional pharmaceutical compoundingtechniques. Excipients can take a wide variety of forms depending on theform of preparation desired for administration. For example, excipientssuitable for use in oral liquid or aerosol dosage forms include, but arenot limited to, water, glycols, oils, alcohols, flavoring agents,preservatives, and coloring agents. Examples of excipients suitable foruse in solid oral dosage forms (e.g., powders, tablets, capsules, andcaplets) include, but are not limited to, starches, sugars,micro-crystalline cellulose, diluents, granulating agents, lubricants,binders, and disintegrating agents.

Because of their ease of administration, tablets and capsules representthe most advantageous oral dosage unit forms, in which case solidexcipients are employed. If desired, tablets can be coated by standardaqueous or nonaqueous techniques. Such dosage forms can be prepared byany of the methods of pharmacy. In general, pharmaceutical compositionsand dosage forms are prepared by uniformly and intimately admixing theactive ingredients with liquid carriers, finely divided solid carriers,or both, and then shaping the product into the desired presentation ifnecessary.

For example, a tablet can be prepared by compression or molding.Compressed tablets can be prepared by compressing in a suitable machinethe active ingredients in a free-flowing form such as powder orgranules, optionally mixed with an excipient. Molded tablets can be madeby molding in a suitable machine a mixture of the powdered compoundmoistened with an inert liquid diluent.

Examples of excipients that can be used in oral dosage forms of theinvention include, but are not limited to, binders, fillers,disintegrants, and lubricants. Binders suitable for use inpharmaceutical compositions and dosage forms include, but are notlimited to, corn starch, potato starch, or other starches, gelatin,natural and synthetic gums such as acacia, sodium alginate, alginicacid, other alginates, powdered tragacanth, guar gum, cellulose and itsderivatives (e.g., ethyl cellulose, cellulose acetate, carboxymethylcellulose calcium, sodium carboxymethyl cellulose), polyvinylpyrrolidone, methyl cellulose, pre-gelatinized starch, hydroxypropylmethyl cellulose, (e.g., Nos. 2208, 2906, 2910), microcrystallinecellulose, and mixtures thereof.

Examples of fillers suitable for use in the pharmaceutical compositionsand dosage forms disclosed herein include, but are not limited to, talc,calcium carbonate (e.g., granules or powder), microcrystallinecellulose, powdered cellulose, dextrates, kaolin, mannitol, silicicacid, sorbitol, starch, pre-gelatinized starch, and mixtures thereof.The binder or filler in pharmaceutical compositions of the invention istypically present in from about 50 to about 99 weight percent of thepharmaceutical composition or dosage form.

Suitable forms of microcrystalline cellulose include, but are notlimited to, the materials sold as AVICEL-PH-101, AVICEL-PH-103 AVICELRC-581, AVICEL-PH-105 (available from FMC Corporation, American ViscoseDivision, Avicel Sales, Marcus Hook, PA), and mixtures thereof. Anspecific binder is a mixture of microcrystalline cellulose and sodiumcarboxymethyl cellulose sold as AVICEL RC-581. Suitable anhydrous or lowmoisture excipients or additives include AVICEL-PH-103™ and Starch 1500LM.

Disintegrants are used in the compositions of the invention to providetablets that disintegrate when exposed to an aqueous environment.Tablets that contain too much disintegrant may disintegrate in storage,while those that contain too little may not disintegrate at a desiredrate or under the desired conditions. Thus, a sufficient amount ofdisintegrant that is neither too much nor too little to detrimentallyalter the release of the active ingredients should be used to form solidoral dosage forms of the invention. The amount of disintegrant usedvaries based upon the type of formulation, and is readily discernible tothose of ordinary skill in the art. Typical pharmaceutical compositionscomprise from about 0.5 to about 15 weight percent of disintegrant,specifically from about 1 to about 5 weight percent of disintegrant.

Disintegrants that can be used in pharmaceutical compositions and dosageforms of the invention include, but are not limited to, agar-agar,alginic acid, calcium carbonate, microcrystalline cellulose,croscarmellose sodium, crospovidone, polacrilin potassium, sodium starchglycolate, potato or tapioca starch, pre-gelatinized starch, otherstarches, clays, other algins, other celluloses, gums, and mixturesthereof.

Lubricants that can be used in pharmaceutical compositions and dosageforms of the invention include, but are not limited to, calciumstearate, magnesium stearate, mineral oil, light mineral oil, glycerin,sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid,sodium lauryl sulfate, talc, hydrogenated vegetable oil (e.g., peanutoil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, andsoybean oil), zinc stearate, ethyl oleate, ethyl laureate, agar, andmixtures thereof. Additional lubricants include, e.g., a syloid silicagel (AEROSIL 200, manufactured by W.R. Grace Co. of Baltimore, Md.), acoagulated aerosol of synthetic silica (marketed by Degussa Co. ofPlano, Tex.), CAB-O-SIL (a pyrogenic silicon dioxide product sold byCabot Co. of Boston, Mass.), and mixtures thereof. If used at all,lubricants are typically used in an amount of less than about 1 weightpercent of the pharmaceutical compositions or dosage forms into whichthey are incorporated.

For oral administration, the compositions can be provided in the form oftablets containing about 1 to about 1000 milligrams of the activeingredient. In other embodiments, the compositions are provided in theform of tablets containing about 1.0, about 5.0, about 10.0, about 15.0.about 20.0, about 25.0, about 50.0, about 75.0, about 100.0, about150.0, about 200.0, about 250.0, about 300.0, about 400.0, about 500.0,about 600.0, about 750.0, about 800.0, about 900.0, or about 1000.0milligrams of the active ingredient for the symptomatic adjustment ofthe dosage to the patient to be treated. The compounds may beadministered on a regimen of 1 to 4 times per day, such as, e.g., onceor twice per day.

Delayed Release Dosage Forms

Active ingredients of the invention can be administered by controlledrelease means or by delivery devices that are well known to those ofordinary skill in the art. Examples include, but are not limited to,those described in U.S. Pat. Nos. 3,845,770; 3,916,899; 3,536,809;3,598,123; 4,008,719; 5,674,533; 5,059,595; 5,591,767; 5,120,548;5,073,543; 5,639,476; 5,354,556; and 5,733,566, each of which isincorporated herein by reference. Such dosage forms can be used toprovide slow or controlled-release of one or more active ingredientsusing, e.g., hydropropylmethyl cellulose, other polymer matrices, gels,permeable membranes, osmotic systems, multilayer coatings,microparticles, liposomes, microspheres, or a combination thereof toprovide the desired release profile in varying proportions. Suitablecontrolled-release formulations known to those of ordinary skill in theart, including those described herein, can be readily selected for usewith the active ingredients of the invention. The invention thusencompasses single unit dosage forms suitable for oral administrationsuch as, but not limited to, tablets, capsules, gelcaps, and capletsthat are adapted for controlled-release.

Controlled-release pharmaceutical products can improve drug therapy overthat achieved by their non-controlled counterparts. Ideally, the use ofan optimally designed controlled-release preparation in medicaltreatment is characterized by a minimum amount of drug substance beingemployed to cure or control the condition in a minimum amount of time.Advantages of controlled-release formulations include extended activityof the drug, reduced dosage frequency, and increased patient compliance.In addition, controlled-release formulations can be used to affect thetime of onset of action or other characteristics, such as blood levelsof the drug, and can thus affect the occurrence of side (e.g., adverse)effects.

Most controlled-release formulations are designed to initially releasean amount of drug (active ingredient) that promptly produces the desiredtherapeutic effect, and gradually and continually release other amountsof drug to maintain this level of therapeutic or prophylactic effectover an extended period of time. In order to maintain this constantlevel of drug in the body, the drug must be released from the dosageform at a rate that will replace the amount of drug being metabolizedand excreted from the body. Controlled-release of an active ingredientcan be stimulated by various conditions including, but not limited to,pH, temperature, enzymes, water, or other physiological conditions orcompounds.

Parenteral Dosage Forms

Parenteral dosage forms can be administered to patients by variousroutes including, but not limited to, subcutaneous, intravenous(including bolus injection), intramuscular, and intra-arterial. Becausetheir administration typically bypasses patients' natural defensesagainst contaminants, parenteral dosage forms can be sterile or capableof being sterilized prior to administration to a patient. Examples ofparenteral dosage forms include, but are not limited to, solutions readyfor injection, dry products ready to be dissolved or suspended in apharmaceutically acceptable vehicle for injection, suspensions ready forinjection, and emulsions. For example, lyophilized sterile compositionssuitable for reconstitution into particulate-free dosage forms aresuitable for administration to humans.

Suitable vehicles that can be used to provide parenteral dosage forms ofthe invention are well known to those skilled in the art. Examplesinclude, but are not limited to: Water for Injection USP; aqueousvehicles such as, but not limited to, Sodium Chloride Injection,Ringer's Injection, Dextrose Injection, Dextrose and Sodium ChlorideInjection, and Lactated Ringer's Injection; water-miscible vehicles suchas, but not limited to, ethyl alcohol, polyethylene glycol, andpolypropylene glycol; and non-aqueous vehicles such as, but not limitedto, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate,isopropyl myristate, and benzyl benzoate.

Compounds that increase the solubility of one or more of the activeingredients disclosed herein can also be incorporated into theparenteral dosage forms of the invention.

Parenteral dosage forms are exemplary for the methods of preventing,treating or managing disease in a cancer patient.

Transdermal and Topical Dosage Forms

Transdermal and topical dosage forms of the invention include, but arenot limited to, creams, lotions, ointments, gels, solutions, emulsions,suspensions, or other forms known to one of skill in the art. See, e.g.,Remington's Pharmaceutical Sciences, 18th eds., Mack Publishing, Easton,Pa. (1990); and Introduction to Pharmaceutical Dosage Forms, 4th ed.,Lea & Febiger, Philadelphia, Pa. (1985). Transdermal dosage formsinclude “reservoir type” or “matrix type” patches, which can be appliedto the skin and worn for a specific period of time to permit thepenetration of a desired amount of active ingredients.

Suitable excipients (e.g., carriers and diluents) and other materialsthat can be used to provide transdermal and topical dosage formsencompassed by this invention are well known to those skilled in thepharmaceutical arts, and depend on the particular tissue to which agiven pharmaceutical composition or dosage form will be applied. Withthat fact in mind, typical excipients include, but are not limited to,water, acetone, ethanol, ethylene glycol, propylene glycol,butane-1,3-diol, isopropyl myristate, isopropyl palmitate, mineral oil,and mixtures thereof to form lotions, tinctures, creams, emulsions, gelsor ointments, which are non-toxic and pharmaceutically acceptable.Moisturizers or humectants also can be added to pharmaceuticalcompositions and dosage forms if desired. Examples of such additionalingredients are well known in the art. See, e.g., Remington'sPharmaceutical Sciences, 18th eds., Mack Publishing, Easton, Pa. (1990).

Depending on the specific tissue to be treated, additional componentsmay be used prior to, in conjunction with, or subsequent to treatmentwith active ingredients of the invention. For example, penetrationenhancers can be used to assist in delivering the active ingredients tothe tissue. Suitable penetration enhancers include, but are not limitedto: acetone; various alcohols such as ethanol, oleyl, andtetrahydrofuryl; alkyl sulfoxides such as dimethyl sulfoxide; dimethylacetamide; dimethyl formamide; polyethylene glycol; pyrrolidones such aspolyvinylpyrrolidone; Kollidon grades (Povidone, Polyvidone); urea; andvarious water-soluble or insoluble sugar esters such as Tween 80(polysorbate 80) and Span 60 (sorbitan monostearate).

The pH of a pharmaceutical composition or dosage form, or of the tissueto which the pharmaceutical composition or dosage form is applied, mayalso be adjusted to improve delivery of one or more active ingredients.Similarly, the polarity of a solvent carrier, its ionic strength, ortonicity can be adjusted to improve delivery. Compounds such asstearates can also be added to pharmaceutical compositions or dosageforms to advantageously alter the hydrophilicity or lipophilicity of oneor more active ingredients so as to improve delivery. In this regard,stearates can serve as a lipid vehicle for the formulation, as anemulsifying agent or surfactant, and as a delivery-enhancing orpenetration-enhancing agent. Different salts, hydrates or solvates ofthe active ingredients can be used to further adjust the properties ofthe resulting composition.

Mucosal Dosage Forms and Lung Delivery

Mucosal dosage forms of the invention include, but are not limited to,ophthalmic solutions, sprays and aerosols, or other forms known to oneof skill in the art. See, e.g., Remington's Pharmaceutical Sciences,18th eds., Mack Publishing, Easton, Pa. (1990); and Introduction toPharmaceutical Dosage Forms, 4th ed., Lea & Febiger, Philadelphia, Pa.(1985). Dosage forms suitable for treating mucosal tissues within theoral cavity can be formulated as mouthwashes or as oral gels. In oneembodiment, the aerosol comprises a carrier. In another embodiment, theaerosol is carrier free.

A compound of the invention can also be administered directly to thelung by inhalation (see, e.g., Tong et al., International PublicationNo. WO 97/39745, and Clark et al, International Publication No. WO99/47196, which are herein incorporated by reference). Foradministration by inhalation, a tricyclic compound can be convenientlydelivered to the lung by a number of different devices. For example, aMetered Dose Inhaler (“MDI”) which utilizes canisters that contain asuitable low boiling propellant, e.g., dichlorodifluoromethane,trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide orother suitable gas can be used to deliver a tricyclic compound directlyto the lung. MDI devices are available from a number of suppliers suchas 3M Corporation, Aventis, Boehringer Ingleheim, Forest Laboratories,Glaxo-Wellcome, Schering Plough and Vectura.

Alternatively, a Dry Powder Inhaler (DPI) device can be used toadminister a tricyclic compound to the lung (see, e.g., Raleigh et al.,Proc. Amer. Assoc. Cancer Research Annual Meeting, 1999, 40, 397, whichis herein incorporated by reference). DPI devices typically use amechanism such as a burst of gas to create a cloud of dry powder insidea container, which can then be inhaled by the patient. DPI devices arealso well known in the art and can be purchased from a number of vendorswhich include, for example, Fisons, Glaxo-Wellcome, Inhale TherapeuticSystems, ML Laboratories, Qdose and Vectura. A popular variation is themultiple dose DPI (“MDDPI”) system, which allows for the delivery ofmore than one therapeutic dose. MDDPI devices are available fromcompanies such as AstraZeneca, GlaxoWellcome, IVAX, Schering Plough,SkyePharma and Vectura. For example, capsules and cartridges of gelatinfor use in an inhaler or insufflator can be formulated containing apowder mix of the compound and a suitable powder base such as lactose orstarch for these systems.

Another type of device that can be used to deliver a tricyclic compoundto the lung is a liquid spray device supplied, for example, by AradigmCorporation. Liquid spray systems use extremely small nozzle holes toaerosolize liquid drug formulations that can then be directly inhaledinto the lung.

In one embodiment, a nebulizer device is used to deliver a tricycliccompound to the lung. Nebulizers create aerosols from liquid drugformulations by using, for example, ultrasonic energy to form fineparticles that can be readily inhaled (see e.g., Verschoyle et al.,British J Cancer, 1999, 80, Suppl 2, 96, which is herein incorporated byreference). Examples of nebulizers include devices supplied bySheffield/Systemic Pulmonary Delivery Ltd. (see Armer et al., U.S. Pat.No. 5,954,047; van der Linden et al., U.S. Pat. No. 5,950,619; and vander Linden et al., U.S. Pat. No. 5,970,974, all of which are hereinincorporated by reference), Aventis, and Batelle Pulmonary Therapeutics.Inhaled compounds, delivered by nebulizer devices, are currently underinvestigation as treatments for aerodigestive cancer (Engelke et al.,Poster 342 at American Association of Cancer Research, San Francisco,Calif., Apr. 1-5, 2000) and lung cancer (Dahl et al., Poster 524 atAmerican Association of Cancer Research, San Francisco, Calif., Apr.1-5, 2000).

In one embodiment, an electrohydrodynamic (“EHD”) aerosol device is usedto deliver a tricyclic compound to the lung. EHD aerosol devices useelectrical energy to aerosolize liquid drug solutions or suspensions(see, e.g., Noakes et al., U.S. Pat. No. 4,765,539; Coffee, U.S. Pat.No. 4,962,885; Coffee, International Publication No. WO 94/12285;Coffee, International Publication No. WO 94/14543; Coffee, InternationalPublication No. WO 95/26234; Coffee, International Publication No. WO95/26235; and Coffee, International Publication No. WO 95/32807, all ofwhich are herein incorporated by reference). The electrochemicalproperties of the compound of the invention formulation may be importantparameters to optimize when delivering this drug to the lung with an EHDaerosol device and such optimization is routinely performed by one ofskill in the art. EHD aerosol devices may more efficiently deliver drugsto the lung than existing pulmonary delivery technologies. Other methodsof intra-pulmonary delivery of a tricyclic compound will be known to theskilled artisan and are within the scope of the invention.

Liquid drug formulations suitable for use with nebulizers and liquidspray devices and EHD aerosol devices will typically include a tricycliccompound with a pharmaceutically acceptable carrier. For instance, thepharmaceutically acceptable carrier is a liquid such as an alcohol,water, polyethylene glycol or a perfluorocarbon. Optionally, anothermaterial can be added to alter the aerosol properties of the solution orsuspension of a tricyclic compound. In some embodiments, this materialis liquid such as an alcohol, glycol, polyglycol or a fatty acid. Othermethods of formulating liquid drug solutions or suspension suitable foruse in aerosol devices are known to those of skill in the art (see,e.g., Biesalski, U.S. Pat. Nos. 5,112,598, and Biesalski, 5,556,611,which are herein incorporated by reference). A compound of the inventioncan also be formulated in rectal or vaginal compositions such assuppositories or retention enemas, e.g., containing conventionalsuppository bases such as cocoa butter or other glycerides.

In addition to the formulations described previously, a tricycliccompound can also be formulated as a depot preparation. Such long actingformulations can be administered by implantation (e.g., subcutaneouslyor intramuscularly) or by intramuscular injection. Thus, e.g., thecompounds can be formulated with suitable polymeric or hydrophobicmaterials (e.g., as an emulsion in an acceptable oil) or ion exchangeresins, or as sparingly soluble derivatives, e.g., as a sparinglysoluble salt.

Other Delivery Systems

Alternatively, other pharmaceutical delivery systems can be employed.Liposomes and emulsions are well known examples of delivery vehiclesthat can be used to deliver a tricyclic compound. Certain organicsolvents such as dimethylsulfoxide can also be employed, althoughpossibly at the risk of greater toxicity. A compound of the inventioncan also be delivered in a controlled release system. In one embodiment,a pump can be used (Sefton, CRC Crit. Ref. Biomed. Eng., 1987, 14, 201;Buchwald et al., Surgery, 1980, 88, 507; Saudek et al., New Engl. J.Med., 1989, 321, 574). In another embodiment, polymeric materials can beused (see Medical Applications of Controlled Release, Langer and Wise(eds.), CRC Press, Boca Raton, Fla. (1974); Controlled DrugBioavailability, Drug Product Design and Performance, Smolen and Ball(eds.), Wiley, New York (1984); Ranger and Peppas, J. Macromol. Sci.Rev. Macromol. Chem., 1983, 23, 61; see also Levy et al., Science, 1985,228, 190; During et al., Ann. Neurol., 1989, 25, 351; Howard et al., J.Neurosurg., 1989, 71, 105). In yet another embodiment, acontrolled-release system can be placed in proximity of the target ofthe compounds of the invention, e.g., the lung, thus requiring only afraction of the systemic dose (see, e.g., Goodson, in MedicalApplications of Controlled Release, supra, vol. 2, pp. 115 (1984)).Other controlled-release system can be used (see, e.g., Langer, Science,1990, 249, 1527).

Suitable excipients (e.g., carriers and diluents) and other materialsthat can be used to provide mucosal dosage forms encompassed by thisinvention are well known to those skilled in the pharmaceutical arts,and depend on the particular site to which or on the method by which agiven pharmaceutical composition or dosage form will be administered.With that fact in mind, typical excipients include, but are not limitedto, water, ethanol, ethylene glycol, propylene glycol, butane-1,3-diol,isopropyl myristate, isopropyl palmitate, mineral oil, and mixturesthereof, which are non-toxic and pharmaceutically acceptable. Examplesof such additional ingredients are well known in the art. See, e.g.,Remington's Pharmaceutical Sciences, 18th eds., Mack Publishing, Easton,Pa. (1990).

The pH of a pharmaceutical composition or dosage form, or of the tissueto which the pharmaceutical composition or dosage form is applied, canalso be adjusted to improve delivery of one or more active ingredients.Similarly, the polarity of a solvent carrier, its ionic strength, ortonicity can be adjusted to improve delivery. Compounds such asstearates can also be added to pharmaceutical compositions or dosageforms to advantageously alter the hydrophilicity or lipophilicity of oneor more active ingredients so as to improve delivery. In this regard,stearates can serve as a lipid vehicle for the formulation, as anemulsifying agent or surfactant, and as a delivery-enhancing orpenetration-enhancing agent. Different salts, hydrates or solvates ofthe active ingredients can be used to further adjust the properties ofthe resulting composition.

Therapeutic Uses of the Tricyclic Compounds

In one embodiment, the invention provides a method for treating orpreventing a condition or disorder associated with the modulation of ahydroxysteroid dehydrogenase by administering to a patient having such acondition or disorder a therapeutically effective amount of a compoundor composition of the invention. In one group of embodiments, conditionsand disorders, including chronic diseases of humans or other species,can be treated with modulators, stimulators, or inhibitors ofhydroxysteroid dehydrogenases, such as 116-HSD1.

Treatment or Prevention of Diabetes

Diabetes and diabetic conditions can be treated or prevented byadministration of a therapeutically effective amount of a tricycliccompound.

Types of diabetes that can be treated or prevented by administering atherapeutically effective amount of a tricyclic compound include type Idiabetes mellitus (juvenile onset diabetes, insulin dependent-diabetesmellitus (IDDM)), type II diabetes mellitus (non-insulin-dependentdiabetes mellitus (NIDDM)), insulinopathies, diabetes associated withpancreatic disorders, diabetes associated with other disorders (such asCushing's Syndrome, acromegaly, pheochromocytoma, glucagonoma, primaryaldosteronism, and somatostatinoma), type A and type B insulinresistance syndromes, lipatrophic diabetes, and diabetes induced byβ-cell toxins.

In one embodiment, the type of diabetes being treated is type IIdiabetes.

Treatment or Prevention of Obesity

Obesity can be treated or prevented by administration of atherapeutically effective amount of a tricyclic compound.

Obesity may have genetic, environmental (e.g., expending less energythan is consumed) and regulatory determinants. Obesity includesexogenous, hyperinsulinar, hyperplasmic, hypothyroid, hypothalamic,symptomatic, infantile, upper body, alimentary, hypogonadal, simple andcentral obesity, hypophyseal adiposity and hyperphagia. Metabolicdisorders, such as hyperlidemia and diabetes, and cardiovasculardisorders, such as hypertension and coronary artery disease, arecommonly associated with obesity.

Complications due to obesity may also be treated or prevented byadministering a therapeutically effective amount of a tricycliccompound. Such complications include, but are not limited to, sleepapnea, Pickwickian syndrome, orthopedic disturbances of weight-bearingand non-weight-bearing joints, and skin disorders resulting fromincreased sweat or skin secretions.

Treatment or Prevention of Other Conditions

Other conditions that can be treated or prevented by administering atherapeutically effective amount of a tricyclic compound include, butare not limited to any condition which is responsive to the modulation,such as inhibition, of a hydroxysteroid dehydrogenase or a specificisoform thereof, and which thereby benefits from administration of sucha modulator. Representative conditions in this regard include, but arenot limited to, metabolic disorders and related cardiovascular riskfactors such as syndrome X, polycystic ovarian disease, eating disorders(e.g., anorexia and bulimia), craniopharyngioma, Prader-Willi syndrome,Frohlich's syndrome, hyperlipidemia, dyslipidemia, hypercholesterolemia,hypertriglyceridemia, low HDL levels, high HDL levels, hyperglycemia,insulin resistance, hyperinsulinemia and Cushing's syndrome; diseasesassociated therewith such as hypertension, atherosclerosis, vascularrestenosis, retinopathy and nephropathy; neurologic disorders such asneurodegenerative disease, neuropathy and muscle wasting; cognitivedisorders such as age-related learning disorders, dementia,neurodegeneration, as well as disorders of cognitive function insubjects ranging from the severely impaired (e.g., Parkinsons's orAlzheimer's associated dementia) to mildly impaired (e.g.,age-associated memory impairment, drug-induced cognitive impairment)(see Sandeep et al., PNAS, electronically available atwww.pnas.org/cgi/doi/10.1073/pnas.0306996101); androgen and/orestrogen-related disorders such as prostate cancer, colon cancer, breastcancer, benign prostatic hyperplasia, ovarian cancer, uterine cancer,and male pseudohermaphrodism; endometriosis; depression; psoriasis;glaucoma; osteoporosis; viral infections; inflammatory disorders; andimmune disorders. The compounds of the invention may also improve thecognitive function of unimpaired subjects (e.g., serve as cognitiveenhancers for the general population).

Additional Therapeutic Agents

In one embodiment, the present method for treating or preventing furthercomprises the administration of a therapeutically effective amount ofone or more additional therapeutic agents useful for treating orpreventing the diseases or disorders disclosed herein. In thisembodiment, the time in which the therapeutic effect of the othertherapeutic agent(s) is exerted overlaps with the time in which thetherapeutic effect of the tricyclic compound is exerted.

The compounds of the invention can be combined or used in combinationwith other agents useful in the treatment, prevention, suppression oramelioration of the conditions or disorders for which compounds of theinvention are useful, including diabetes, obesity, glaucoma,osteoporosis, cognitive disorders, immune disorders, depression andthose pathologies noted above.

Such other agents, or drugs, may be administered, by a route and in anamount commonly used therefor, simultaneously or sequentially with atricyclic compound. In one embodiment, a pharmaceutical compositioncontains one or more such other agents or drugs in addition to thecompound of the invention when a tricyclic compound is usedcontemporaneously with one or more other agents or drugs. Accordingly,the pharmaceutical compositions of the invention include those that alsocontain one or more other active ingredients or therapeutic agents, inaddition to a tricyclic compound.

In an embodiment, for the treatment or prevention of diabetes, atricyclic compound can be administered with one or more additionaltherapeutic agents including, but not limited to, anti-diabetic agentssuch as insulin, inhaled insulin (Exubera®), insulin mimetics, insulinsecretogues, sulfonylureas (e.g., glyburide, meglinatide, glimepiride,gliclazide, glipizide, gliquidone, chloropropresponsivemide,tolbutamide, acetohexamide, glycopyramide, carbutamide, glibonuride,glisoxepid, glybuthiazole, glibuzole, glyhexamide, glymidine,glypinamide, phenbutamide, tolcylamide and tolazamide), biguanides(e.g., metformin (Glucophage®)), α-glucosidase inhibitors (e.g.,acarbose, voglibose and miglitol), thiazolidinone compounds (e.g.,rosiglitazone (Avandia®), troglitazone (Rezulin®), ciglitazone,pioglitazone (Actos®) and englitazone), prandial glucose regulators(e.g., repaglinide and nateglinide), and glucagon receptor antagonists.

In another embodiment, for the treatment or prevention of obesity, atricyclic compound can be administered with one or more additionaltherapeutic agents, including, but not limited to, β3 adrenergicreceptor agonists, leptin or derivatives thereof, neuropeptide Y (e.g.,NPY5) antagonists, and mazindol.

Examples of other therapeutic agents that may be combined with atricyclic compound, either administered separately or in the samepharmaceutical composition, include, but are not limited to: (i)cholesterol-lowering agents such as HMG-CoA reductase inhibitors (e.g.,lovastatin, simvastatin (Zocor®), pravastatin, fluvastatin, atorvastatin(Lipitor®) and other statins), bile acid sequestrants (e.g.,cholestyramine and colestipol), vitamin B₃ (also known as nicotinicacid, or niacin), vitamin B₆ (pyridoxine), vitamin B₁₂ (cyanocobalamin),fibric acid derivatives (e.g., gemfibrozil, clofibrate, fenofibrate andbenzafibrate), probucol, nitroglycerin, and inhibitors of cholesterolabsorption (e.g., beta-sitosterol and acylCoA-cholesterolacyltransferase (ACAT) inhibitors such as melinamide), HMG-CoA synthaseinhibitors, squalene epoxidase inhibitors and squalene synthetaseinhibitors; (ii) antithrombotic agents such as thrombolytic agents(e.g., streptokinase, alteplase, anistreplase and reteplase), heparin,hirudin and warfarin derivatives, β-blockers (e.g., atenolol), βadrenergic agonists (e.g., isoproterenol), angiotensin II antagonists,ACE inhibitors and vasodilators (e.g., sodium nitroprusside, nicardipinehydrochloride, nitroglycerin and enaloprilat); (iii) PPAR agonists(e.g., PPAR_(γ) and PPAR_(δ) agonists); (iv) DP antagonists; (v)lubricants or emollients such as petrolatum and lanolin, keratolyticagents, vitamin D₃ derivatives (e.g., calcipotriene and calcipotriol(Dovonex®)), PUVA, anthralin (Drithrocreme®), etretinate (Tegison®) andisotretinoin; (vi) glaucoma therapies such as cholinergic agonists(e.g., pilocarpine and carbachol), cholinesterase inhibitors (e.g.,physostigmine, neostigmine, demacarium, echothiophate iodide andisofluorophate), carbonic anhydrase inhibitors (e.g., acetazolamide,dichlorphenamide, methazolamide, ethoxzolamide and dorzolamide),non-selective adrenergic agonists (e.g., epinephrine and dipivefrin),α₂-selective adrenergic agonists (e.g., apraclonidine and brimonidine),β-blockers (e.g., timolol, betazolol, levobunolol, carteolol andmetipranolol), prostaglandin analogs (e.g., latanoprost) and osmoticdiuretics (e.g., glycerin, mannitol and isosorbide); corticosteroidssuch as beclomethasone, methylprednisolone, betamethasone, prednisone,prenisolone, dexamethasone, fluticasone and hydrocortisone, andcorticosteroid analogs such as budesonide; (vii) immunosuppressants suchas cyclosporine (cyclosporine A, Sandimmune®, Neoral®), tacrolimus(FK-506, Prograf®), rapamycin (sirolimus, Rapamune®) and other FK-506type immunosuppressants, and mycophenolates (e.g., mycophenolate mofetil(CellCepte®); (viii) non-steroidal antiinflammatory agents (NSAIDs) suchas propionic acid derivatives (e.g., alminoprofen, benoxaprofen,bucloxic acid, carprofen, fenbufen, fenoprofen, fluprofen, flurbiprofen,ibuprofen, indoprofen, ketoprofen, miroprofen, naproxen, oxaprozin,pirprofen, pranoprofen, suprofen, tiaprofenic acid and tioxaprofen),acetic acid derivatives (e.g., indomethacin, acemetacin, alclofenac,clidanac, diclofenac, fenclofenac, fenclozic acid, fentiazac, furofenac,ibufenac, isoxepac, oxpinac, sulindac, tiopinac, tolmetin, zidometacinand zomepirac), fenamic acid derivatives (e.g., flufenamic acid,meclofenamic acid, mefenamic acid, niflumic acid and tolfenamic acid),biphenylcarboxylic acid derivatives (e.g., diflunisal and flufenisal),oxicams (e.g., isoxicam, piroxicam, sudoxicam and tenoxican),salicylates (e.g., acetylsalicylic acid and sulfasalazine), andpyrazolones (e.g., apazone, bezpiperylon, feprazone, mofebutazone,oxyphenbutazone and phenylbutazone); (ix) cyclooxygenase-2 (COX-2)inhibitors such as celecoxib (Celebrex®) and rofecoxib (Vioxx®); (xi)inhibitors of phosphodiesterase type IV (PDE-IV); (xii) opioidanalgesics such as codeine, fentanyl, hydromorphone, levorphanol,meperidine, methadone, morphine, oxycodone, oxymorphone, propoxyphene,buprenorphine, butorphanol, dezocine, nalbuphine and pentazocine; (xiii)hepatoprotective agents; and (xiv) other compounds such as5-aminosalicylic acid and prodrugs thereof.

The weight ratio of the compound of the invention to one or moreadditional active ingredients may be varied and will depend upon theeffective dose of each ingredient. Generally, an effective dose of eachwill be used. Thus, for example, when a tricyclic compound is combinedwith an NSAID, the weight ratio of the compound of the invention to theNSAID will generally range from about 1000:1 to about 1:1000, such as,e.g., about 200:1 to about 1:200. Combinations of a tricyclic compoundand one or more additional active ingredients will generally also bewithin the aforementioned range, but in each case, an effective dose ofeach active ingredient should be used.

Kits

The invention encompasses kits that can simplify the administration of atricyclic compound, or composition thereof, to a patient.

A typical kit of the invention comprises a unit dosage of a tricycliccompound. In one embodiment, the unit dosage form is in a container,which can be sterile, containing a therapeutically effective amount of atricyclic compound and a pharmaceutically acceptable vehicle. In anotherembodiment, the unit dosage form is in a container containing atherapeutically effective amount of a tricyclic compound as a lyophilateor pharmaceutically acceptable salt. In this instance, the kit canfurther comprise another container that contains a solution useful forthe reconstitution of the lyophilate or dissolution of the salt. The kitcan also comprise a label or printed instructions for use of thetricyclic compound.

In a further embodiment, the kit comprises a unit dosage form of acomposition of the invention.

Kits of the invention can further comprise one or more devices that areuseful for administering the unit dosage forms of a tricyclic compound,or a composition thereof. Examples of such devices include, but are notlimited to, a syringe, a drip bag, a patch or an enema, which optionallycontain the unit dosage forms.

The present invention is not to be limited in scope by the specificembodiments disclosed in the examples, which are intended asillustrations of a few embodiments of the invention, and any embodimentsthat are functionally equivalent are within the scope of this invention.Indeed, various modifications of the invention in addition to thoseshown and described herein will become apparent to those skilled in theart and are intended to fall within the scope of the appended claims. Tothis end, it should be noted that one or more hydrogen atoms or methylgroups may be omitted from the drawn structures consistent with acceptedshorthand notation of such organic compounds, and that one skilled inthe art of organic chemistry would readily appreciate their presence.

Preparation of Tricyclic Compounds of Formula (I)

Representative synthetic schemes, methods, reactions, reagents, andreaction conditions for the preparation of compounds of formula (I) aredescribed below. Those skilled in the art will recognize that there area variety of synthetic schemes, methods, reactions, reagents, andreaction conditions available to synthesize compounds of formula (I)described herein and represented in the claims.

To facilitate a reaction or the formation of particular functionalgroups, or to avoid undesired side reactions, protecting (or “blocking”)groups may be employed. The use of protecting groups to protectfunctional groups from undesired side reactions is well known in theart. Protecting groups may be used for any functional group on anycompound in any step of the process for synthesizing a final product,depending on the compatibility of the protecting groups with particularreagents, reaction conditions, and reaction sequences, as is known inthe art.

EXAMPLE 1 Preparation of2-(4-(4-cyclohexyloxazol-5-yl)phenyl)-1,1,1-trifluoro-propan-2-ol4-(1,1,1-Trifluoro-2-hydroxypropan-2-yl)benzaldehyde

(a) To a mixture of methyl 4-acetylbenzoate (8.9 g, 50.0 mmol, 1.0equiv.) and CF₃SiMe₃ (14.2 g, 100.0 mmol, 2.0 equiv.) in THF (100 mL)was added TBAF (75 mL, 1.0 M solution in THF, 75.0 mmol, 1.5 equiv.)dropwise at 0° C. After being stirred at r.t. for 12 h, the mixture wasdiluted with CH₂Cl₂ (100 mL). The organic layer was washed withsaturated aqueous NaHCO₃ and brine, dried and concentrated in vacuo. Theresidue was purified by flash column chromatography (15% EtOAc/hexane)to give the ester as a colorless liquid: ¹H NMR (400 MHz, CDCl₃) δ 8.07(d, J=8.5 Hz, 2 H), 7.67 (d, J=8.5 Hz, 2 H), 3.93 (s, 3 H), 2.70 (br,1H), 1.80 (s, 3H); MS (ESI) 249.1 (M+H)⁺.

(b)(1) To a solution of the ester obtained above (7.44 g, 30 mmol, 1.0equiv.) in dry THF (50 mL) was slowly added LiAlH₄ (36 mL, 1.0 Msolution in Et₂O, 36 mmol, 1.2 equiv.) at 0° C. After being stirred for4 h at 0° C., the reaction mixture was quenched (H₂O and 2N NaOH),extracted (EtOAc), dried (Na₂SO₄) and concentrated in vacuo. The crudematerial was purified by flash column chromatography (40% EtOAc/hexane)to provide the primary alcohol.

(2) The Dess-Martin periodinane (7.86 g, 18.5 mmol, 1.2 equiv.) wasadded to a solution of the alcohol obtained above (3.4 g, 15.5 mmol, 1.0equiv.) in CH₂Cl₂ (10 mL) and THF (5 mL) at 0° C. After being stirred atr.t. for 24 h, the mixture was quenched with saturated aqueous NaHCO₃and diluted with CH₂Cl₂. The aqueous layer was extracted with CH₂Cl₂,and the combined organic layers were washed with NaCl, dried with sodiumsulfate, filtered and concentrated in vacuo. The crude material waspurified by flash column chromatography (20% EtOAc/hexanes) to affordthe aldehyde as a white solid: ¹H NMR (400 MHz, CDCl₃) δ 10.3 (s, 1 H),8.00 (d, J=6.0 Hz, 12 H), 7.87 (d, J=6.0 Hz, 1 H), 2.85 (s, 1 H), 1.92(s, 3 H).

2-(4-(4-Cyclohexyloxazol-5-yl)phenyl)-1,1,1-trifluoropropan-2-ol

(a) NaH (0.8 g, 20.0 mmol, 60% dispersion in oil, 2.0 equiv.) was addedto a solution of toluenesulphonylmethyl isocyanide (1.95 g, 10.0 mmol,1.0 equiv.) in DMSO (10 mL) and Et₂O (10 mL) over 5 minutes at 0° C. andthe reaction mixture was stirred while warming to r.t. for 20 minutes.Cyclohexyl iodide (1.55 mL, 12 mmol, 1.2 equiv) was added dropwise over3 minutes and the resulting mixture was stirred at r.t. for 2 h. Thereaction mixture was then diluted with ethyl acetate (250 mL), and theseparated organic layer was washed with water (60 mL), dried over MgSO₄,filtered and concentrated under reduced pressure. The residue waspurified by flash chromatography (20% EtOAc/hexane) to give the productas a white solid: ¹H NMR (400 MHz, CDCl₃) δ 7.88 (d, J=8.3 Hz, 2 H),7.43 (d, J=8.3 Hz, 2 H), 4.30 (d, J=3.5 Hz, 1 H), 2.50 (s, 3 H), 2.42(m, 1 H), 2.15 (1 H), 1.85-1.71 (m, 4 H), 1.44-1.19 (m, 5 H).

(b) The alkylated TosMIC obtained above (480 mg, 1.73 mmol, 1.2 equiv.)was dissolved in MeOH (2 mL) and treated with sodium methoxide (25%solution in MeOH, 0.94 mL, 3 equiv.), and4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)benzaldehyde (314 mg, 1.44 mmol,1.0 equiv.) was then added. After being heated at 80° C. for 2 h, thereaction mixture was then cooled to r.t., diluted with ethyl acetate (80mL) and washed with brine. The separated organic layer was dried overNa₂SO₄, filtered and concentrated under reduced pressure. The residuewas purified by flash chromatography (30% EtOAC/hexane) to provide2-(4-(4-cyclohexyloxazol-5-yl)phenyl)-1,1,1-trifluoropropan-2-ol as awhite solid: ¹H NMR (400 MHz, CDCl₃) δ 7.85 (s, 1 H), 7.70 (d, J=8.4 Hz,2 H), 7.62 (d, J=8.4 Hz, 2 H), 2.90 (m, 1 H), 2.88 (s, 1 H), 1.90 (m, 4H), 1.84 (s, 3 H), 1.76 (m, 3 H), 1.36 (m, 3 H).

EXAMPLE 2 Preparation of1,1,1-trifluoro-2-(4-(4-(1-tosylpiperidin-4-yl)oxazol-5-yl)phenyl)propan-2-ol4-Bromo-1-tosylpiperidine

4-Bromopiperidine (5.75 g, 23.5 mmol) was dissolved in pyridine (50 mL)and treated with tosyl chloride (5.8 g, 30.5 mmol). The reaction mixturewas stirred for 12 h at r.t. and then diluted with dichloromethane (150mL) and HCl (1 M aqueous solution, 50 mL). The organic layer was washedwith brine (80 mL), dried over MgSO₄, filtered and concentrated underreduced pressure. The residue was purified by flash chromatography (40%EtOAc/hexane) to give 4-bromo-1-tosylpiperidine as a white solid: ¹H NMR(400 MHz, CDCl₃) δ 7.66 (d, J=8.2 Hz, 2H), 7.34 (d, J=8.2 Hz, 2H),4.27-4.24 (m, 1H), 3.20-3.17 (m, 2H), 3.13-3.11 (m, 2H), 2.46 (s, 3H),2.23-2.17 (m, 2H), 2.08-2.05 (m, 2H); MS (ESI) 318.0 (M+H)⁺.

4-(Isocyano(tosyl)methyl)-1-tosylpiperidine

NaH (0.92 g, 23.07 mmol, 60% dispersion in oil) was added to DMF (70 mL)in one portion at 0° C. Toluenesulphonylmethyl isocyanide (3.0 g, 15.38mmol) in DMF (12 mL) was added dropwise over 5 minutes and the mixturewas stirred while warming to r.t. for 20 minutes.4-Bromo-1-tosylpiperidine (4.46 g, 18.4 mmol) in DMF (10 mL) was thenadded dropwise over 3 minutes and the resulting mixture was stirred atr.t. for 16 h. The mixture was then diluted with ethyl acetate (250 mL)and LiCl (1 M aqueous solution, 60 mL), and the separated organic layerwas washed with water (60 mL), dried over MgSO₄, filtered andconcentrated under reduced pressure. The residue was purified by flashchromatography (20% EtOAc/hexane) to provide4-(isocyano(tosyl)methyl)-1-tosylpiperidine as a white solid: ¹H NMR(400 MHz, CDCl₃) δ 7.79 (d, J=8.0 Hz, 2H), 7.61 (d, J=7.6 Hz, 2H), 7.38(d, J=8.0 Hz, 2H), 7.32 (d, J=7.6 Hz, 2H), 4.34 (d, J=4.0 Hz, 1H),3.87-3.84 (m, 2H), 2.44 (s, 3H), 2.43 (s, 3H), 2.30-2.10 (m, 2H),2.10-2.0 (m, 1H), 2.0-1.70 (m, 4H); MS (ESI) 451.1 (M+H+H₂O)⁺.

1,1,1-Trifluoro-2-(4-(4-(1-tosylpiperidin-4-yl)oxazol-5-yl)phenyl)propan-2-ol

4-(Isocyano(tosyl)methyl)-1-tosylpiperidine (260 mg, 0.73 mmol) wasdissolved in MeOH (6 mL) and treated with sodium methoxide (1.0 Msolution in MeOH, 0.7 mL), and4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)benzaldehyde (159 mg, 0.73 mmol)was then added. After being stirred at 80° C. for 2 h, the mixture wasthen cooled to r.t. and diluted with ethyl acetate (80 mL) and saturatedaqueous NaHCO₃ (30 mL). The separated organic layer was dried overMgSO₄, filtered and concentrated under reduced pressure. The residue waspurified by flash chromatography (15% EtOAc/hexane) to provide1,1,1-trifluoro-2-(4-(4-(1-tosylpiperidin-4-yl)oxazol-5-yl)phenyl)propan-2-olas a white solid: ¹H NMR (400 MHz, CDCl₃) δ 7.83 (s, 1H), 7.69-7.65 (m,2H), 7.51-7.49 (m, 2H), 7.36-7.33 (m, 4H), 3.90 (d, J=11.7 Hz, 2H),3.30-3.28 (s, 1H), 2.79 (tt, J=3.9 Hz, 11.7 Hz, 1H), 2.45 (s, 3H), 2.37(td, J=2.3 Hz, 12.1 Hz, 2H), 2.17-2.07 (m, 2H), 1.85 (d, J=12.1 Hz, 2H),1.80 (s, 3H); MS (ESI) 495.1 (M+H)⁺.

EXAMPLE 3 Preparation of2-(4-(4-cyclohexylisoxazol-5-yl)phenyl)-1,1,1-trifluoropropan-2-ol

(a) Methyl 4-acetylbenzoate (20.0 g, 112.3 mmol) was dissolved inbenzene (250 mL), and ethylene glycol (6.3 mL, 112.3 mmol) andpara-toluenesulfonic acid (1.92 g, 11.2 mmol) were added in one portion.After being heated at reflux for 3 h using a Dean-Stark trap, themixture was then allowed to cool and washed successively with saturatedaqueous NaHCO₃, water and brine. The separated organic layer was driedover MgSO₄, filtered and concentrated under reduced pressure. Theresidue was purified by flash chromatography (15% EtOAc/hexane) to givethe ketal as a colorless oil: ¹H NMR (400 MHz, CDCl₃) δ 7.98 (d, J=8.6Hz, 2H), 7.53 (d, J=8.6 Hz, 2H), 4.04-4.01 (m, 2H), 3.88 (s, 3H),3.75-3.71 (m, 2H), 1.62 (s, 3H); (ESI) 223.1 (M+H)⁺.

(b) The ketal obtained above (18.5 g, 83.3 mmol) was slurried withN,O-dimethylhydroxylamine hydrochloride (10.15 g, 104.1 mmol) inanhydrous THF (150 mL) and cooled to ⁻10° C. Isopropyl magnesiumchloride (125 mL, 2.0 M solution in THF, 250 mmol) was added dropwisevia an addition funnel over 20 min. The mixture was allowed to warm tor.t. and stirred for 2 hours and then quenched with saturated aqueousNH₄Cl (100 mL), water (60 mL) and diluted with ethyl acetate (80 mL).The separated aqueous layer was extracted with ethyl acetate (300 mL),dried over MgSO₄, filtered and concentrated under reduced pressure. Theresidue was purified by flash chromatography (20% EtOAc/hexane) toprovide the benzamide as a colorless oil: ¹H NMR (400 MHz, CDCl₃) δ 7.66(d, J=8.6 Hz, 2H), 7.53 (d, J=8.6 Hz, 2H), 4.08-4.06 (m, 2H), 3.80-3.78(s, 2H), 3.59 (s, 3H), 3.38 (s, 3H), 1.67 (s, 3H), MS (ESI) 252.1(M+H)⁺.

(c) (Bromomethyl)cyclohexane (8.3 mL, 60 mmol) was added to a mixture ofMg (1.44 g, 60 mmol) and I₂ (10 mg) in anhydrous THF (100 mL) at r.t.under a N₂ atmosphere. The mixture was stirred for 2 hours and thenadded to a solution of the benzamide obtained above (5.0 g, 20 mmol) inanhydrous THF (80 mL). The resulting reaction mixture was stirred for 2hours at r.t. and then diluted with ethyl acetate (300 mL), saturatedaqueous NH₄Cl (60 mL) and water (140 mL). The separated organic layerwas dried over MgSO₄, filtered and concentrated under reduced pressure.The residue was purified by flash chromatography (15% EtOAc/hexane) togive the ketone as a white solid: ¹H NMR (400 MHz, CDCl₃) δ 8.57 (s,1H), 7.61 (dd, 1H, J=7.0 Hz, 7.0 Hz, 1H), 7.31 (d, J=8.0 Hz, 1H), 7.11(dd, J=5.4 Hz, 5.4 Hz, 1H), 4.58 (s, 2H); 4.41 (s, 2H), 2.69-2.67 (m,1H), 2.13-2.06 (m, 3H), 1.90-1.60 (m, 6H), 1.49-1.46 (m, 2H), 0.44-0.33(m, 4H); MS (ESI) 289.1 (M+H)⁺.

(d) The ketone obtained above (1.6 g, 5.55 mmol) was dissolved in ethylformate (20 mL), and sodium ethoxide (755 mg, 11.1 mmol) was added inone portion. The reaction mixture was stirred for 16 h at r.t. and thendiluted with ethyl acetate (250 mL) and saturated aqueous NaHCO₃ (100mL). The separated organic layer was dried over MgSO₄, filtered andconcentrated under reduced pressure. The residue was purified by flashchromatography (10% EtOAc/hexane) to provide the ketoaldehyde as acolorless oil: ¹H NMR (400 MHz, CDCl₃) δ 9.60 (d, J=4.7 Hz, 1H), 7.88(d, J=8.2 Hz, 2H), 7.54 (d, J=8.2 Hz, 2H), 4.10 (dd, J=4.7 Hz, 9.4 Hz,1H), 4.00-3.97 (m, 2H), 3.73-3.67 (m, 2H), 2.40-2.31 (m, 1H), 1.69-1.57(m, 5H), 1.57 (s, 3H), 1.21-0.95 (m, 5 H); MS (ESI) 317.2 (M+H)⁺.

(e) Hydroxylamine hydrochloride (48.4 mg, 0.71 mmol) was added to asolution of the ketoaldehyde obtained above (150 mg, 0.48 mmol) inpyridine (1 mL). After being heated at 80° C. for 1 h, the mixture wascooled to 23° C. and quenched with 3 N HCl. The aqueous layer wasextracted with EtOAc, and the combined organic layers were washed withNaCl, dried with sodium sulfate, filtered and concentrated in vacuo. Thecrude material was dissolved in THF (2 mL) and conc. HCl (0.5 mL) andstirred for 1 h. The reaction mixture was quenched with saturatedaqueous NaHCO₃ and diluted with CH₂Cl₂. The aqueous layer was extractedwith EtOAc, and the combined organic layers were washed with NaCl, driedwith sodium sulfate, filtered and concentrated in vacuo. The crudematerial was purified by flash column chromatography (20% EtOAc/hexanes)to afford the ketoisoxazole as a white solid.

(f) To a solution of the ketoisoxazole obtained above (80 mg, 0.26 mmol)and CF₃TMS (72.7 mg, 0.52 mmol) in THF (1 mL) at 0° C. was added TBAF(383 μL, 1 M solution in THF, 0.38 mmol) dropwise. After being stirredat r.t. for 12 h, the mixture was quenched with saturated aqueous NaHCO₃and diluted with EtOAc. The aqueous layer was extracted with EtOAc, andthe combined organic layers were washed with NaCl, dried with sodiumsulfate, filtered and concentrated in vacuo. The crude material waspurified by flash column chromatography (20% EtOAc/hexanes) to afford2-(4-(4-cyclohexylisoxazol-5-yl)phenyl)-1,1,1-trifluoropropan-2-ol as awhite solid: ¹H NMR (400 MHz, CDCl₃) δ 8.26 (s, 1 H), 7.75 (m, 4 H),2.79 (m, 1 H), 2.71 (s, 1 H), 1.95-1.78 (m, 6 H), 1.85 (s, 3 H),1.46-1.28 (m, 4 H).

EXAMPLE 4 Preparation of2-(4-(4-cyclohexylisoxazol-5-yl)phenyl)propan-2-ol

Methyl lithium (159 μL, 1.6 M solution in Et₂O, 0.25 mmol) was addeddropwise to a solution of1-(4-(4-cyclohexylisoxazol-5-yl)phenyl)ethanone obtained above (57 mg,0.21 mmol) in THF (2 mL) at 0° C. After stirring for 15 min, another100μL of the methyl lithium solution was added to the reaction mixture.After being stirred for an additional 1 h at 0° C., the mixture wasquenched with saturated aqueous NH₄Cl and diluted with EtOAc. Theaqueous layer was extracted with EtOAc, and the combined organic layerswere washed with NaCl, dried with magnesium sulfate, filtered andconcentrated in vacuo to give a yellow oil. The crude material waspurified by flash column chromatography (20%→40% EtOAc/hexanes) toafford 2-(4-(4-cyclohexylisoxazol-5-yl)phenyl)propan-2-ol as a colorlessoil: ¹H NMR (400 MHz, CDCl₃) δ 8.23 (s, 1H), 7.62 (m, 4H), 2.77 (m, 1H),2.09 (m, 1H), 1.86 (m, 5H), 1.63 (s, 6H), 1.37 (m, 5H).

EXAMPLE 5 Preparation of2-(4-(4-cyclohexyl-3-methylisoxazol-5-yl)phenyl)-1,1,1-trifluoropropan-2-ol

(a)(1) Methylmagnesium bromide (830 μL, 3 M solution in Et₂O, 2.5 mmol)was added dropwise to a solution of the ketoaldehyde obtained above (395mg, 1.25 mmol) in Et₂O (3 mL) at 0° C. After approximately half of theGrignard reagent had been added, 2 mL of THF was added and the reactionmixture was warmed to 23° C., at which point the remaining Grignardreagent was added. After being stirred for 30 min, the mixture wasquenched with saturated aqueous NH₄Cl and diluted with EtOAc. Theaqueous layer was extracted with EtOAc, and the combined organic layerswere washed with NaCl, dried with magnesium sulfate, filtered andconcentrated in vacuo to give a yellow oil. The crude material waspurified by flash column chromatography (5% →25% EtOAc/hexanes) toafford the alcohol as colorless oil.

(2) The Dess-Martin periodinane (257 mg, 0.60 mmol) was added to amixture of the alcohol obtained above (134 mg, 0.40 mmol) and sodiumbicarbonate (67 mg, 0.80 mmol) in CH₂Cl₂ (10 mL) at 0° C. After beingstirred for 2 h, the mixture was quenched with saturated aqueous NaHCO₃and diluted with CH₂Cl₂. The aqueous layer was extracted with CH₂Cl₂,and the combined organic layers were washed with NaCl, dried withmagnesium sulfate, filtered and concentrated in vacuo to give a yellowoil. The crude material was purified by flash column chromatography (15%→25% EtOAc/hexanes) to afford the diketone as a colorless oil.

(b)(1) Hydroxylamine hydrochloride (50 mg, 0.72 mmol) was added to asolution of the diketone obtained above (118 mg, 0.36 mmol) in pyridine(4 mL) and the resulting mixture was heated to 80° C. After beingstirred for 19 h, the mixture was cooled to 23° C. and quenched with 3 NHCl. The aqueous layer was extracted with EtOAc, and the combinedorganic layers were washed with NaCl, dried with magnesium sulfate,filtered and concentrated in vacuo to afford the crude oxime.

(2) The crude oxime was dissolved in THF (2 mL), 2 N HCl (1 mL) wasadded, and the solution was stirred for 4 h. The reaction mixture wasquenched with saturated aqueous NaHCO₃ and diluted with CH₂Cl₂. Theaqueous layer was extracted with CH₂Cl₂, and the combined organic layerswere washed with NaCl, dried with magnesium sulfate, filtered andconcentrated in vacuo. The crude material was purified by flash columnchromatography (8% →25% EtOAc/hexanes) to afford the ketoisoxazole as awhite solid.

(3) To a solution of the ketoisoxazole obtained above (66 mg, 0.23 mmol)and CF₃TMS (45 μL, 0.30 mmol) in THF (1 mL) at 0° C. was added TBAF (340μL, 1 M solution in THF, 0.34 mmol) dropwise. After being stirred for 1h, the mixture was quenched with saturated aqueous NaHCO₃ and dilutedwith CH₂Cl₂. The aqueous layer was extracted with CH₂Cl₂, and thecombined organic layers were washed with NaCl, dried with magnesiumsulfate, filtered and concentrated in vacuo. The crude material waspurified by flash column chromatography (15% →30% EtOAc/hexanes) tofurnish the title alcohol as a white foam: ¹H NMR (400 MHz, CD₃OD) δ7.80 (d, J=8.3 Hz, 2H), 7.59 (m, 2H), 2.76 (tt, J=12.2, 3.5 Hz, 1H),2.41 (s, 3H), 1.79 (s, 3H), 1.76 (m, 7H), 1.35 (m, 3H); anal. calcd forC₁₉H₂₂F₃NO₂: C, 64.58; H, 6.28; N, 3.96. found: C, 64.49; H, 6.27; N,3.93.

EXAMPLE 6 Preparation of2-(4-(4-cyclohexylisoxazol-3-yl)phenyl)propan-2-ol

(a) The ketoaldehyde obtained above (0.17 g, 0.54 mmol) was dissolved inbenzene (5 mL) and treated with ethylene glycol (0.03 mL, 0.54 mmol) andpara-toluenesulfonic acid (9 mg, 0.054 mmol). After being heated at 80°C. for 12 h, the mixture was cooled to r.t. and diluted with ethylacetate (60 mL) and saturated aqueous NaHCO₃ (30 mL). The separatedorganic layer was dried over MgSO₄, filtered and concentrated underreduced pressure. The residue was purified by flash chromatography (10%EtOAc/hexane) to give the acetal as a colorless oil: ¹H NMR (400 MHz,CDCl₃) δ 7.88 (d, J=8.6 Hz, 2H), 7.54 (d, J=8.2 Hz, 2H), 5.25 (d, J=7.0Hz, 1H), 4.06-4.02 (m, 2H), 3.94-3.74 (m, 6H), 3.55 (dd, J=7.0 Hz, 7.0Hz, 1H), 2.03-1.94 (m, 2H), 1.73-1.59 (m, 4H), 1.64 (s, 3H), 1.26-1.03(m, 5 H); LC MS (ESI) 361.1 (M+H)⁺.

(b)(1) The acetal (320 mg, 0.89 mmol) was dissolved in pyridine (5 mL)and treated with hydroxylamine hydrochloride (200 mg, 2.89 mmol). Afterbeing heated at 100° C. for 16 h, the reaction mixture was then cooledto r.t. and diluted with ethyl acetate (100 mL) and water (50 mL). Theseparated organic layer was dried (MgSO4), filtered and concentratedunder reduced pressure to provide the crude oxime.

(2) The crude oxime was dissolved in anhydrous THF (5 mL) and treatedwith conc. HCl (0.5 mL). The resulting mixture was stirred at r.t. for14 h and then diluted with ethylacetate (100 mL) and saturated aqueousNaHCO₃ (50 mL). The separated organic layer was dried over MgSO₄,filtered and concentrated under reduce pressure. The residue waspurified by flash chromatography (5% EtOAc/hexane) to afford the reverseketoisoxazole as a white solid: ¹H NMR (400 MHz, CDCl₃) δ 8.26 (s, 1H),8.06 (d, J=5.8 Hz, 2H), 7.72 (d, J=5.8 Hz, 2H), 2.66 (s, 3H), 2.65-2.62(m, 1H), 1.92-1.89 (m, 2H), 1.76-1.60 (m, 3H), 1.30-1.22 (m, 5H); MS(ESI) 270.1 (M+H)⁺.

(3) The reverse ketoisoxazole (140 mg, 0.52 mmol) was dissolved inanhydrous THF (10 mL) and cooled to 0° C. The reaction mixture wastreated with methyl lithium (1.6 M solution in THF, 0.62 mL, 1.04 mmol)and stirred for 2.5 h at r.t. The reaction was then diluted with ethylacetate (60 mL) and water (30 mL), and the separated organic layer wasdried over MgSO₄, filtered and concentrated under reduced pressure. Theresidue was purified by flash chromatography (10% EtOAc/hexane) toprovide 2-(4-(4-cyclohexylisoxazol-3-yl)phenyl)propan-2-ol as a whitesolid: ¹H NMR (400 MHz, CDCl₃) δ 8.23 (s, 1H), 7.60 (s, 4H), 2.61-2-56(m, 1H), 1.93-1.89 (m, 2H), 1.76-1.62 (m, 3H), 1.63 (s, 6H), 1.30-1.22(m, 5H); MS (ESI) 286.1 (M+H)⁺.

EXAMPLE 7 Preparation of2-(4-(5-cyclohexyl-2-methylthiazol-4-yl)phenyl)-1,1,1-trifluoropropan-2-ol

(a) To a solution of2-cyclohexyl-1-(4-(2-methyl-1,3-dioxolan-2-yl)phenyl)ethanone obtainedabove (1.5 g, 5.2 mmol, 1.0 equiv.) in DCM (10 mL) was added pyridiniumtribromide (1.66 g, 5.2 mmol, 1.0 equiv.). After being stirred at 25° C.for 3 h, the resulting mixture was diluted (sat. NaHCO₃) and extracted(10% MeOH/DCM). The organic layer was dried (Na₂SO₄) and concentratedunder reduced pressure. Purification by flash chromatography (SiO₂, 5-9%EtOAc/hexane) gave the α-bromo ketone as a colorless oil.

(b) To a solution of thioacetamide (150 mg, 2.0 mmol, 1.0 equiv.) inMeOH (2 mL) was added a solution of the α-bromo ketone obtained above(740 mg, 2.0 mmol, 1.0 equiv.) in MeOH (2 mL) dropwise at 50° C. Afterbeing stirred at 50° C. for 4 h, the resulting mixture was diluted (sat.NaHCO₃) and extracted (10% MeOH/DCM). The organic layer was dried(Na₂SO₄) and concentrated under reduced pressure. Purification by flashchromatography (SiO₂, 5-20% EtOAc/hexane) gave the ketothiazole as acolorless oil.

(c) To a mixture of the ketothiazole (30 mg, 0.1 mmol, 1.0 equiv.) andTMS-CF₃ (21.3 mg, 0.15 mmol, 1.5 equiv.) in THF (1 mL) was added TBAF(1.0 M in THF, 0.2 mL, 0.2 mmol, 2.0 equiv.). After being stirred at 25°C. for 0.5 h, the resulting mixture was diluted (sat. NaHCO₃) andextracted (10% MeOH/DCM). The organic layer was dried (Na₂SO₄) andconcentrated under reduced pressure. Purification by flashchromatography (SiO₂, 10-20% EtOAc/hexane) afforded the title alcohol asa white solid: ¹H NMR (CDCl₃) δ 7.64 (d, J=8.2 Hz, 2 H), 7.57 (d, J=8.2Hz, 2 H), 3.02 (m, 1 H), 2.86 (s, 1H), 2.71 (s, 3H), 2.02 (m, 2H),1.84-1.74 (m, 5H), 1.75-1.47 (m, 6H).

BIOLOGICAL EXAMPLES

Procedures Useful for Biological Evaluation of Tricyclic Compounds

In addition to the extensive literature disclosing the role of HSDs invarious diseases and disorders, described herein are assays useful fortesting the tricyclic compounds of the present invention.

Assays

Inhibition of 11β-HSD1 (11β-Hydroxysteroid Dehydrogenase Type 1)Activity in vitro

Inhibition of 11β-HSD1 activity was examined by quantitativedetermination, by an SPA (scintillation proximity assay) system, of thesuppressive action on the conversion from cortisone to cortisol usinghuman 11β-HSD1 (hereinafter recombinant 11β-HSD1) expressed using abaculo-virus system as an enzyme source. For the reaction, a reagent wasadded to a 96-well plate (96-well Opti-plates™-96 (Packard)) to thefollowing final concentration and a volume of 100 μl, and the reactiontranspired at room temperature for 90 min. The reaction solution usedwas 0.1 μg/ml recombinant 11β-HSD1, 500 μM NADPH, 16 nM ³H cortisone(Amersham Biosciences, 1.78 Tbq/mol) dissolved in 0.1% BSA(Sigma)-containing PBS and the test drug was 2 μl of a compound solution(dissolved in DMSO). After 90 min, the reaction was stopped by addingPBS (40 μl,containing 0.1% BSA (Sigma)) containing 0.08 μg ofanti-cortisol mouse monoclonal antibody (East Coast Biologics), 365 μgSPA PVT mouse antibody-binding beads (Amersham Biosciences) and 175 μMcarbenoxolone (Sigma) to the reaction solution. After completion of thereaction, the plate was incubated overnight at room temperature and theradioactivity was measured by Topcount (Packard). For control, the value(0% inhibition) of the well containing 2 μl of DMSO instead of the testdrug was used, and for positive control, the value (100% inhibition) ofthe well containing carbenoxolone instead of the test drug at the finalconcentration of 50 μM was used. The inhibition (%) of the test drug wascalculated by ((value of control−value of test drug)/(value ofcontrol−value of positive control))×100(%). The IC₅₀ value was analyzedusing a computer-based curve fitting software.

This example provides assays that are useful in evaluating and selectinga compound that modulates 11β-HSD1.

Biochemical 11β-HSD1 Assay by SPA

Recombinant human, mouse and rat 11β-HSD1 were expressed in baculovirusexpression system, isolated by affinity purification and used as theenzyme sources for cortisone to cortisol conversion in vitro.³H-Cortisone (Amersham Bioscience, 1.78 Tbq/mol. 49 Ci/mmol) was used asthe substrate, and a monoclonal anti-cortisol antibody and thescintillation proximity assay (SPA) system were used to detect theproduct of the 11β-HSD1-catalyzed reaction, ³H-cortisol. Reactions tookplace at room temperature for 90 min. in 96-well Opti-plates™-96(Packard) in 100 μL volume with 2 μL test compounds or control in DMSO,0.1 μg/mL 11β-HSD1 protein, 500 μM NADPH and 16 nM radioactivecortisone, in PBS buffer supplemented with 0.1% BSA (Sigma). Reactionwas stopped with the addition of 40 μL buffer containing 0.08 μganti-cortisol monoclonal antibody (East Coast Biologics), 365 μg SPA PVTantibody-binding beads (Amersham Biosciences) and 175 μM carbenoxolone(Sigma).

Plates were incubated at room temperature overnight before being read ona Topcount (Packard). The point of 50% inhibition of 11β-HSD1 enzymeactivity (IC₅₀) was determined by computer-based curve fitting.

Cell-Based 11β-HSD1 Assay by Spa

This cell-based assay measures the conversion of ³H-cortisone to³H-cortisol in a HEK-293 cell line stably overexpressing humanrecombinant 11β-HSD1. HEK-293 cells were grown in DMEM/F12 supplementedwith 10% fetal bovine serum, and plated onto poly-D-lysine-coated96-well assay plates (Costar 3903), 100,000 cells per well in 50 μLassay media (phenol-free DMEM/F12 (Invitrogen)+0.2% BSA+1%antibiotic-antimycotic solutions). The solution was incubated at 37° C.for 24 h, and the reaction was initiated by the addition of 25 μL ofassay media containing a compound of desired concentration and 25 μL ofassay media containing 40 nM of ³H-cortisone to each well. The reactionmixture was incubated at 37° C. for 90 min. and the reaction terminatedby the addition of 25 μL of assay media containing 0.2 μg ofanti-cortisol monoclonal antibody (East Coast Biologics), 500 μg SPA PVTantibody-binding beads (Amersham Biosciences) and 500 μM carbenoxolone(Sigma).

Plates were incubated at room temperature for at least 2 h before beingread on Topcount (Packard). The point of 50% inhibition of 11β-HSD1enzyme activity (IC₅₀) was determined by computer-based curve fitting.

Scintillation Proximity Assay (SPA)

[1,2(n)-³H]-cortisone was purchased from Amersham Pharmacia Biotech.Anti-cortisol monoclonal mouse antibody, clone 6D6.7, was obtained fromImmunotech, and Scintillation Proximity Assay (SPA) beads coated withmonoclonal antimouse antibodies were purchased from Amersham PharmaciaBiotech. NADPH, tetrasodium salt was obtained from Calbiochem, andglucose-6-phosphate (G-6-P) was supplied by Sigma. The human11-β-hydroxysteroid dehydrogenase type 1 enzyme (11-β-HSD1) wasexpressed in Pichia pastoris. 18-β-glycyrrhetinic acid (GA) was obtainedfrom Sigma. The serial dilutions of the compounds were performed on aTecan Genesis RSP 150. Compounds to be tested were dissolved in DMSO (1mM) and diluted in 50 mM Tris-HCl, pH 7.2, containing 1 mM EDTA.

The multiplication of plates was done on a WallacQuadra. The amount ofthe product [³H]-cortisol bound to the beads was determined in aPackard, Top Count microplate liquid scintillation counter.

The 11-β-HSD1 enzyme assay was carried out in 96-well microtiter plates(Packard, Optiplate) in a total well volume of 220 μL and contained 30mM Tris-HCl, pH 7.2, with 1 mM EDTA, a substrate mixture tritiatedCortisone/NADPH (175 nM/181 μM), G-6-P (1 mM) and inhibitors in serialdilutions (9 to 0.15 μM). Reactions were initiated by the addition ofhuman 11-β-HSD1, either as Pichia pastoris cell homogenate or microsomesprepared from Pichia pastoris (the final amount of enzyme used wasvaried between 0.057 to 0.11 mg/mL). Following mixing, the plates wereshaken for 30 to 45 minutes at room temperature. The reactions wereterminated with 10 μL 1 mM GA stop solution. Monoclonal mouse antibodywas then added (10 μL of 4 μM) followed by 100 μL of SPA beads(suspended according to the manufacturers instructions). Appropriatecontrols were set up by omitting the 11-β-HSD1 to obtain thenon-specific binding (NSB) value.

The plates were covered with plastic film and incubated on a shaker for30 minutes, at room temperature, before counting. The amount of[³H]-cortisol bound to the beads was determined in a microplate liquidscintillation counter. The calculation of the K, values for theinhibitors was performed by use of Activity Base. The K_(i) value iscalculated from IC₅₀ and the K_(m) value is calculated using the ChengPrushoff equation (with reversible inhibition that follows theMichaelis-Menten equation): K_(i)=IC₅₀(1+[S]/K_(m)) (Cheng, Y. C.;Prushoff, W. H., Biochem. Pharmacol. 1973, 22, 3099-3108). The IC₅₀ ismeasured experimentally in an assay wherein the decrease of the turnoverof cortisone to cortisol is dependent on the inhibition potential ofeach substance.

Cloning, Expression and Purification of 11β-HSD1

The expression and purification of the murine enzyme is described by J.Zhang et al., Biochemistry 2005, 44, 6948-57. The expression andpurification of the human enzyme is similar to that of the murinesequence.

Enzyme Assay

The IC₅₀ and K_(i) of the compounds are determined by the followingmethod:

1. Prepare an Assay Buffer, (pH 7.2, 50 mM Tris-HCL, 1 mM EDTA) fresheach week.

2. Prepare the following solutions:

-   -   NADPH (Sigma, 200 μM)    -   ³H-Cortisone (Amersham Biosciences, 45 Ci/mmol, 200 nM)    -   Enzyme Prep (20 nM for human, 10 nM for mouse)    -   Cortisol Antibody (East Coast Biologicals, 1:50 dilution)    -   Anti-mouse SPA beads (Amersham Biosciences, 15 mg/ml)    -   18β-Glycyrrhetinic acid (“GA”) (Aldrich, 1 μM)    -   Compound Stock Solution (10 mM in DMSO), serially diluted in        Assay Buffer. Each compound is normally tested at six different        concentrations (10 μM to 0.1 nM).        -   All of the solutions and dilutions are made in the Assay            Buffer.

3. Assay is run using white/white, 96-well assay plates (Corning) in atotal volume of 100 μL.

4. Into each well of a 96-well plate is added Assay Buffer (30 μL),compound (10 μL), NADPH (10 μL), and ³H-cortisone (10 μL).

5. Initiate reaction by adding 40 μL of HSD-1 enzyme prep to the wells.

6. The plate is covered with tape and incubated on an orbital shaker for1 h at room temperature.

7. After 1 h, the tape is removed and anti-cortisol antibody (10 μL), GAsolution (10 μL and SPA bead preparation (100 μL) are added.

8. The plate is incubated (30 min) on an orbital shaker at roomtemperature.

9. The counts are read on a TopCount NXT reader.

10. A dose-response curve is first plotted using the Graphpad Prismsoftware to generate the IC₅₀ values.

11. With the IC₅₀ value and the known K_(m) value for the substrate andHSD1 enzyme, an estimated K_(i) can be calculated with the Chen andPrusoff equation {K_(i)=IC₅₀/[1+(substrate/K_(m))]}.

The compounds of the present invention show inhibitory activity againstthe 11β-HSD1 enzyme in the assays, with IC₅₀ values ranging from 55 nMto 1000 nM.

We claim:
 1. A compound selected from the group consisting of:


2. A pharmaceutical composition comprising a therapeutically effectiveamount of a compound according to claim 1, and a pharmaceuticallyacceptable carrier.
 3. A pharmaceutical composition comprising atherapeutically effective amount of a compound according to claim 1, andone or more additional therapeutic agents.
 4. The pharmaceuticalcomposition according to claim 3, wherein the one or more additionaltherapeutic agents are useful for treating a condition or disorderselected from the group consisting of diabetes, syndrome X, obesity,polycystic ovarian disease, an eating disorder, craniopharyngioma,Prader-Willi syndrome, Frohlich's syndrome, hyperlipidemia,dyslipidemia, hypercholesterolemia, hypertriglyceridemia, low HDLlevels, high HDL levels, hyperglycemia, insulin resistance,hyperinsulinemia, Cushing's syndrome, hypertension, atherosclerosis,vascular restenosis, retinopathy, nephropathy, neurodegenerativedisease, neuropathy, muscle wasting, a cognitive disorder, dementia,depression, psoriasis, glaucoma, osteoporosis, a viral infection, aninflammatory disorder, and an immune disorder.